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Ra YE, Bang YJ. Balancing Act of the Intestinal Antimicrobial Proteins on Gut Microbiota and Health. J Microbiol 2024; 62:167-179. [PMID: 38630349 DOI: 10.1007/s12275-024-00122-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 05/15/2024]
Abstract
The human gut houses a diverse and dynamic microbiome critical for digestion, metabolism, and immune development, exerting profound effects on human health. However, these microorganisms pose a potential threat by breaching the gut barrier, entering host tissues, and triggering infections, uncontrolled inflammation, and even sepsis. The intestinal epithelial cells form the primary defense, acting as a frontline barrier against microbial invasion. Antimicrobial proteins (AMPs), produced by these cells, serve as innate immune effectors that regulate the gut microbiome by directly killing or inhibiting microbes. Abnormal AMP production, whether insufficient or excessive, can disturb the microbiome equilibrium, contributing to various intestinal diseases. This review delves into the complex interactions between AMPs and the gut microbiota and sheds light on the role of AMPs in governing host-microbiota interactions. We discuss the function and mechanisms of action of AMPs, their regulation by the gut microbiota, microbial evasion strategies, and the consequences of AMP dysregulation in disease. Understanding these complex interactions between AMPs and the gut microbiota is crucial for developing strategies to enhance immune responses and combat infections within the gut microbiota. Ongoing research continues to uncover novel aspects of this intricate relationship, deepening our understanding of the factors shaping gut health. This knowledge has the potential to revolutionize therapeutic interventions, offering enhanced treatments for a wide range of gut-related diseases.
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Affiliation(s)
- Ye Eun Ra
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Ye-Ji Bang
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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2
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Rosenberg L, Liu C, Sharma R, Wood C, Vyhlidal CA, Gaedigk R, Kho AT, Ziniti JP, Celedón JC, Tantisira KG, Weiss ST, McGeachie MJ, Kechris K, Sharma S. Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma. Int J Mol Sci 2023; 24:7727. [PMID: 37175432 PMCID: PMC10178351 DOI: 10.3390/ijms24097727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/14/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA-mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA-mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value < 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA-mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.
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Affiliation(s)
- Lynne Rosenberg
- Department of Pediatrics and Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Cuining Liu
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Rinku Sharma
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Cheyret Wood
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
| | | | - Roger Gaedigk
- Children’s Mercy Hospital and Clinics, Kansas City, MO 64108, USA
| | - Alvin T. Kho
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - John P. Ziniti
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Juan C. Celedón
- Division of Pediatric Pulmonary Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Kelan G. Tantisira
- Division of Pediatric Respiratory Medicine, Rady Children’s Hospital, University of California, San Diego, CA 92123, USA
| | - Scott T. Weiss
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Michael J. McGeachie
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Katerina Kechris
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Sunita Sharma
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Han H, Cummings S, Shade KTC, Johnson J, Qian G, Gans J, Shankara S, Escobedo J, Zarazinski E, Bodinizzo R, Bangari D, Bryce P, Hicks A. Cellular mechanisms and effects of IL-4 receptor blockade in experimental conjunctivitis evoked by skin inflammation. JCI Insight 2023; 8:163495. [PMID: 36626228 PMCID: PMC9977427 DOI: 10.1172/jci.insight.163495] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 01/03/2023] [Indexed: 01/11/2023] Open
Abstract
Ocular surface diseases, including conjunctivitis, are recognized as common comorbidities in atopic dermatitis (AD) and occur at an increased frequency in patients with AD treated with biologics targeting IL-4 receptor α (IL-4Rα) or IL-13. However, the inflammatory mechanisms underlying this pathology are unknown. Here, we developed a potentially novel mouse model of skin inflammation-evoked conjunctivitis and showed that it is dependent on CD4+ T cells and basophils. Blockade of IL-4Rα partially attenuated conjunctivitis development, downregulated basophil activation, and led to a reduction in expression of genes related to type 2 cytokine responses. Together, these data suggest that an IL-4Rα/basophil axis plays a role in the development of murine allergic conjunctivitis. Interestingly, we found a significant augmentation of a number of genes that encode tear proteins and enzymes in anti-IL-4Rα-treated mice, and it may underlie the partial efficacy in this model and may represent candidate mediators of the increased frequency of conjunctivitis following dupilumab in patients with AD.
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Affiliation(s)
- Hongwei Han
- Sanofi, Immunology and Inflammation Research Therapeutic Area, Cambridge, Massachusetts, USA
| | - Sheila Cummings
- Sanofi, Global Discovery Pathology, Translational In-vivo Models Platform, Cambridge, Massachusetts, USA
| | - Kai-Ting C. Shade
- Sanofi, Immunology and Inflammation Research Therapeutic Area, Cambridge, Massachusetts, USA
| | - Jennifer Johnson
- Sanofi, Global Discovery Pathology, Translational In-vivo Models Platform, Cambridge, Massachusetts, USA
| | - George Qian
- Sanofi, Immunology and Inflammation Research Therapeutic Area, Cambridge, Massachusetts, USA
| | - Joseph Gans
- Sanofi, Translational Science Single Cell & Functional Genomics, Cambridge, Massachusetts, USA
| | - Srinivas Shankara
- Sanofi, Translational Science Single Cell & Functional Genomics, Cambridge, Massachusetts, USA
| | - Javier Escobedo
- Sanofi, Translational Science Single Cell & Functional Genomics, Cambridge, Massachusetts, USA
| | - Erik Zarazinski
- Sanofi, In-vivo Research Center, Translational In-vivo Models Platform, Cambridge, Massachusetts, USA
| | - Renee Bodinizzo
- Sanofi, In-vivo Research Center, Translational In-vivo Models Platform, Cambridge, Massachusetts, USA
| | - Dinesh Bangari
- Sanofi, Global Discovery Pathology, Translational In-vivo Models Platform, Cambridge, Massachusetts, USA
| | - Paul Bryce
- Sanofi, Immunology and Inflammation Research Therapeutic Area, Cambridge, Massachusetts, USA
| | - Alexandra Hicks
- Sanofi, Immunology and Inflammation Research Therapeutic Area, Cambridge, Massachusetts, USA
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Zhu G, Cai H, Ye L, Mo Y, Zhu M, Zeng Y, Song X, Yang C, Gao X, Wang J, Jin M. Small Proline-Rich Protein 3 Regulates IL-33/ILC2 Axis to Promote Allergic Airway Inflammation. Front Immunol 2022; 12:758829. [PMID: 35126350 PMCID: PMC8810634 DOI: 10.3389/fimmu.2021.758829] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open
Abstract
Small proline-rich proteins (SPRRs), components of cornified cell envelope precursors, have recently been found to participate in airway diseases. However, their role in allergic airway inflammatory conditions remains unknown. Here, we explored the expression of SPRR3 in house dust mite (HDM)-sensitized/challenged mice and attempted to elucidate the regulatory role of SPRR3 in allergic airway inflammation. SPRR3 was identified via bioinformatics analysis of Gene Expression Omnibus (GEO) databases and further confirmed to be upregulated in the lungs of asthmatic mice. Knockdown of SPRR3 via the intratracheal route significantly inhibited eosinophils in bronchoalveolar lavage fluid (BALF) and suppressed the expressions of type 2 cytokines (IL-4, IL-5, and IL-13) in BALF and lung tissues. Further, SPRR3 knockdown reduced the expression of IL-33 and further attenuated the activation of the PI3K/AKT/NF-κB signaling pathway in the recruitment of group 2 innate lymphoid cells (ILC2s) to inhibit allergic airway inflammation. In vitro, SPRR3 siRNA could alleviate HDM-induced inflammatory responses in BEAS-2B cells. This study reveals the regulatory role of SPRR3 in allergic airway inflammation, identifying this protein as a potential novel therapeutic target for asthma.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Jian Wang
- *Correspondence: Meiling Jin, ; Jian Wang,
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5
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Yao L, Yan J, Cheng F, Gan L, Huang Y, Zheng L, Fang N. Small Proline-Rich Protein 2B Facilitates Gastric Adenocarcinoma Proliferation via MDM2-p53/p21 Signaling Pathway. Onco Targets Ther 2021; 14:1453-1463. [PMID: 33664578 PMCID: PMC7924129 DOI: 10.2147/ott.s281032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/13/2021] [Indexed: 12/29/2022] Open
Abstract
Background The small proline-rich protein 2B (SPRR2B) was firstly reported as a member of the cross-linked envelope protein in keratinocytes. The effect of SPRR2B in gastric adenocarcinoma (GC) remains unclear. This study initially explored the clinical significance of SPRR2B in GC patients as well as its role in tumor progression. Methods Immunohistochemistry was performed to characterize the expression of SPRR2B in GC tissues and adjacent tissues. The relationship between SPRR2B expression and clinicopathological features of GC patients was analyzed by Chi-square test. Kaplan-Meier method and Cox regression analyses were utilized to identify the prognostic factors of GC. Overexpression and knockdown assays were conducted to investigate possible signaling pathways downstream of SPRR2B. Flow cytometry assays were performed to evaluate cell cycle and apoptosis. Xenograft experiments were performed to validate tumor-related role of SPRR2B in vivo. Results Both mRNA and protein levels of SPRR2B in cancerous tissue were significantly higher than those in non-cancerous tissues. Meanwhile, SPRR2B expression was significantly associated with tumor size and tumor stage. Survival analysis revealed SPRR2B as one of the independent prognosis factors for overall survival of GC patients. Cellular and xenografts data implicated that silencing SPRR2B blocked the cell cycle of GC cells perhaps through MDM2-p53/p21-CDK1 pathway, while overexpressing SPRR2B exhibited opposite effects. Conclusion Our data suggest that SPRR2B may serve as a novel prognostic marker in GC, which functions at least partially by MDM2-p53/p21-CDK1 signaling pathway.
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Affiliation(s)
- Ling Yao
- Department of Gastroenterology, Third Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi Province, People's Republic of China
| | - Jinhua Yan
- Department of Hematology, Third Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi Province, People's Republic of China
| | - Fei Cheng
- Department of Gastroenterology, Third Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi Province, People's Republic of China
| | - Lihong Gan
- Department of Gastroenterology, Third Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi Province, People's Republic of China
| | - Yaqin Huang
- Department of Gastroenterology, Third Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi Province, People's Republic of China
| | - Li Zheng
- Department of Gastroenterology, Third Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi Province, People's Republic of China
| | - Nian Fang
- Department of Gastroenterology, Third Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi Province, People's Republic of China
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Huynh KM, Wong ACY, Wu B, Horschman M, Zhao H, Brooks JD. Sprr2f protects against renal injury by decreasing the level of reactive oxygen species in female mice. Am J Physiol Renal Physiol 2020; 319:F876-F884. [PMID: 33017192 DOI: 10.1152/ajprenal.00318.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Renal injury leads to chronic kidney disease, with which women are not only more likely to be diagnosed than men but have poorer outcomes as well. We have previously shown that expression of small proline-rich region 2f (Sprr2f), a member of the small proline-rich region (Sprr) gene family, is increased several hundredfold after renal injury using a unilateral ureteral obstruction (UUO) mouse model. To better understand the role of Sprr2f in renal injury, we generated a Sprr2f knockout (Sprr2f-KO) mouse model using CRISPR-Cas9 technology. Sprr2f-KO female mice showed greater renal damage after UUO compared with wild-type (Sprr2f-WT) animals, as evidenced by higher hydroxyproline levels and denser collagen staining, indicating a protective role of Sprr2f during renal injury. Gene expression profiling by RNA sequencing identified 162 genes whose expression levels were significantly different between day 0 and day 5 after UUO in Sprr2f-KO mice. Of the 162 genes, 121 genes were upregulated after UUO and enriched with those involved in oxidation-reduction, a phenomenon not observed in Sprr2f-WT animals, suggesting a protective role of Sprr2f in UUO through defense against oxidative damage. Consistently, bilateral ischemia-reperfusion injury resulted in higher serum blood urea nitrogen levels and higher tissue reactive oxygen species in Sprr2f-KO compared with Sprr2f-WT female mice. Moreover, cultured renal epithelial cells from Sprr2f-KO female mice showed lower viability after oxidative damage induced by menadione compared with Sprr2f-WT cells that could be rescued by supplementation with reduced glutathione, suggesting that Sprr2f induction after renal damage acts as a defense against reactive oxygen species.
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Affiliation(s)
- Kieu My Huynh
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Anny Chuu-Yun Wong
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Bo Wu
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Marc Horschman
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - Hongjuan Zhao
- Department of Urology, School of Medicine, Stanford University, Stanford, California
| | - James D Brooks
- Department of Urology, School of Medicine, Stanford University, Stanford, California
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7
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Effects of the dietary fibre inulin and Trichuris suis products on inflammatory responses in lipopolysaccharide-stimulated macrophages. Mol Immunol 2020; 121:127-135. [PMID: 32200170 DOI: 10.1016/j.molimm.2020.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/04/2020] [Accepted: 03/11/2020] [Indexed: 01/15/2023]
Abstract
Consumption of fermentable dietary fibres, such as inulin, or administration of helminth products (e.g. Trichuris suis ova) have independently been shown to alleviate inflammation in vivo. We recently found that dietary inulin and T. suis infection in pigs co-operatively suppressed type-1 inflammatory responses in the gut, suggesting the potential of dietary components to augment anti-inflammatory responses induced by certain helminths. Here, we explored whether T. suis antigens and inulin could directly suppress inflammatory responses in vitro in a cooperative manner. T. suis soluble products (TsSP) strongly suppressed lipopolysaccharide (LPS)-induced IL-6 and TNF-α secretion from murine macrophages and induced an anti-inflammatory phenotype as evidenced by transcriptomic and gene pathway analyses. Inulin regulated the expression of a small number of genes and transcriptional pathways in macrophages after exposure to LPS, but did not enhance the suppressive activity of TsSP, either directly or in co-culture experiments with intestinal epithelial cells. Culture of macrophages with short-chain fatty acids, the products of microbial fermentation of inulin, did however appear to enhance TsSP-mediated inhibition of TNF-α production. Our results confirm a direct role for helminth products in suppressing inflammatory responses in macrophages. In contrast, inulin had little capacity to directly modulate LPS-induced responses. Our results suggest distinct mode-of-actions of T. suis and inulin in regulating inflammatory responses, and that the role of inulin in modulating the response to helminth infection may be dependent on other factors such as production of metabolites by the gut microbiota.
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8
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Herrmann M, Babler A, Moshkova I, Gremse F, Kiessling F, Kusebauch U, Nelea V, Kramann R, Moritz RL, McKee MD, Jahnen-Dechent W. Lumenal calcification and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity. PLoS One 2020; 15:e0228503. [PMID: 32074120 PMCID: PMC7029858 DOI: 10.1371/journal.pone.0228503] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 01/16/2020] [Indexed: 12/22/2022] Open
Abstract
The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP)-rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization (calcification). The mutant mouse strain D2,Ahsg-/- combines fetuin-A deficiency with the calcification-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue calcification. Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. We analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/- mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis. Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.
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Affiliation(s)
- Marietta Herrmann
- Helmholtz Institute for Biomedical Engineering, Biointerface Lab, RWTH Aachen University Hospital, Aachen, Germany
| | - Anne Babler
- Helmholtz Institute for Biomedical Engineering, Biointerface Lab, RWTH Aachen University Hospital, Aachen, Germany
| | - Irina Moshkova
- Helmholtz Institute for Biomedical Engineering, Biointerface Lab, RWTH Aachen University Hospital, Aachen, Germany
| | - Felix Gremse
- Helmholtz Institute for Biomedical Engineering, Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany
| | - Fabian Kiessling
- Helmholtz Institute for Biomedical Engineering, Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany
| | - Ulrike Kusebauch
- Institute for Systems Biology, Seattle, Washington, United States of America
| | - Valentin Nelea
- Faculty of Dentistry, Faculty of Medicine (Dept. of Anatomy and Cell Biology), McGill University, Montreal, Quebec, Canada
| | - Rafael Kramann
- Division of Nephrology, RWTH Aachen University Hospital, Aachen, Germany
| | - Robert L. Moritz
- Institute for Systems Biology, Seattle, Washington, United States of America
| | - Marc D. McKee
- Faculty of Dentistry, Faculty of Medicine (Dept. of Anatomy and Cell Biology), McGill University, Montreal, Quebec, Canada
| | - Willi Jahnen-Dechent
- Helmholtz Institute for Biomedical Engineering, Biointerface Lab, RWTH Aachen University Hospital, Aachen, Germany
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9
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Ramakrishnan VR, Gonzalez JR, Cooper SE, Barham HP, Anderson CB, Larson ED, Cool CD, Diller JD, Jones K, Kinnamon SC. RNA sequencing and pathway analysis identify tumor necrosis factor alpha driven small proline-rich protein dysregulation in chronic rhinosinusitis. Am J Rhinol Allergy 2017; 31:283-288. [PMID: 28859701 PMCID: PMC5590176 DOI: 10.2500/ajra.2017.31.4457] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder in which many pathways contribute to end-organ disease. Small proline-rich proteins (SPRR) are polypeptides that have recently been shown to contribute to epithelial biomechanical properties relevant in T-helper type 2 inflammation. There is evidence that genetic polymorphism in SPRR genes may predict the development of asthma in children with atopy and, correlatively, that expression of SPRRs is increased under allergic conditions, which leads to epithelial barrier dysfunction in atopic disease. METHODS RNAs from uncinate tissue specimens from patients with CRS and control subjects were compared by RNA sequencing by using Ingenuity Pathway Analysis (n = 4 each), and quantitative polymerase chain reaction (PCR) (n = 15). A separate cohort of archived sinus tissue was examined by immunohistochemistry (n = 19). RESULTS A statistically significant increase of SPRR expression in CRS sinus tissue was identified that was not a result of atopic presence. SPRR1 and SPRR2A expressions were markedly increased in patients with CRS (p < 0.01) on RNA sequencing, with confirmation by using real-time PCR. Immunohistochemistry of archived surgical samples demonstrated staining of SPRR proteins within squamous epithelium of both groups. Pathway analysis indicated tumor necrosis factor (TNF) alpha as a master regulator of the SPRR gene products. CONCLUSION Expression of SPRR1 and of SPRR2A is increased in mucosal samples from patients with CRS and appeared as a downstream result of TNF alpha modulation, which possibly resulted in epithelial barrier dysfunction.
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Affiliation(s)
- Vijay R. Ramakrishnan
- From the Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado
| | - Joseph R. Gonzalez
- From the Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado
| | - Sarah E. Cooper
- From the Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado
| | - Henry P. Barham
- From the Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado
| | - Catherine B. Anderson
- Rocky Mountain Taste and Smell Center, Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado
| | - Eric D. Larson
- Rocky Mountain Taste and Smell Center, Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado
| | - Carlyne D. Cool
- Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, and
| | - John D. Diller
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado
| | - Kenneth Jones
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado
| | - Sue C. Kinnamon
- From the Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado
- Rocky Mountain Taste and Smell Center, Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado
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10
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Guan Y, Jin X, Liu X, Huang Y, Wang M, Li X. Uncovering potential key genes associated with the pathogenesis of asthma: A microarray analysis of asthma-relevant tissues. Allergol Immunopathol (Madr) 2017; 45:152-159. [PMID: 27842724 DOI: 10.1016/j.aller.2016.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 08/03/2016] [Accepted: 08/19/2016] [Indexed: 01/18/2023]
Abstract
BACKGROUND The present study aimed to discover more potential genes associated with the pathogenesis of asthma. METHODS The microarray data of GSE67940 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in bronchial alveolar lavage cells from patients with mild-moderate asthma (notSA) and severe asthma (SA) compared with normal controls (NC), respectively. Functional and pathway enrichment analysis, protein-protein interaction (PPI) network analysis were performed upon the identified up- and down-regulated DEGs. Besides, the gene association network based on the common up-regulated and down-regulated genes was generated and transcriptional regulatory pairs of overlapping DEGs in the PPI network were identified. RESULTS A total of 104 DEGs (30 up- and 74 down-regulated genes) were identified in notSA vs. NC. Additionally, 2796 DEGs were screened out in SA vs. NC group, including 320 up-regulated DEGs, and 135 down-regulated DEGs. Specially, 41 overlapping DEGs were screened out in notSA vs. NC and SA vs. NC, including 16 common up-regulated genes and 25 common down-regulated genes. No pathways were enriched by the DEGs in notSA vs. NC. DEGs in SA vs. NC were associated with cytokine-cytokine receptor interaction. VEGFA was a hub protein in both the PPI networks of DEGs in notSA vs. NC and SA vs. NC. Gene association network showed that signalling pathways and cytokine-cytokine receptor interaction were involved in. The overlapping VEGFA, and IFRD1, and ZNF331 were regulated by more TFs. CONCLUSION Genes such as VEGFA, and IFRD1, and ZNF331 may be associated with pathogenesis of asthma.
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Liu Q, Liu Y, Wang X, Xu J, Zhou W. Genes involved in keratinization, keratinocyte and epithelium differentiation are aberrantly regulated in oral lichen planus. Genes Genomics 2015. [DOI: 10.1007/s13258-015-0303-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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12
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Yue Y, Guo T, Liu J, Guo J, Yuan C, Feng R, Niu C, Sun X, Yang B. Exploring Differentially Expressed Genes and Natural Antisense Transcripts in Sheep (Ovis aries) Skin with Different Wool Fiber Diameters by Digital Gene Expression Profiling. PLoS One 2015; 10:e0129249. [PMID: 26076016 PMCID: PMC4468096 DOI: 10.1371/journal.pone.0129249] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 05/06/2015] [Indexed: 11/18/2022] Open
Abstract
Wool fiber diameter (WFD) is the most important economic trait of wool. However, the genes specifically controlling WFD remain elusive. In this study, the expression profiles of skin from two groups of Gansu Alpine merino sheep with different WFD (a super-fine wool group [FD = 18.0 ± 0.5 μm, n=3] and a fine wool group [FD=23.0 ± 0.5 μm, n=3]) were analyzed using next-generation sequencing-based digital gene expression profiling. A total of 40 significant differentially expressed genes (DEGs) were detected, including 9 up-regulated genes and 31 down-regulated genes. Further expression profile analysis of natural antisense transcripts (NATs) showed that more than 30% of the genes presented in sheep skin expression profiles had NATs. A total of 7 NATs with significant differential expression were detected, and all were down-regulated. Among of 40 DEGs, 3 DEGs (AQP8, Bos d2, and SPRR) had significant NATs which were all significantly down-regulated in the super-fine wool group. In total of DEGs and NATs were summarized as 3 main GO categories and 38 subcategories. Among the molecular functions, cellular components and biological processes categories, binding, cell part and metabolic process were the most dominant subcategories, respectively. However, no significant enrichment of GO terms was found (corrected P-value >0.05). The pathways that were significantly enriched with significant DEGs and NATs were mainly the lipoic acid metabolism, bile secretion, salivary secretion and ribosome and phenylalanine metabolism pathways (P < 0.05). The results indicated that expression of NATs and gene transcripts were correlated, suggesting a role in gene regulation. The discovery of these DEGs and NATs could facilitate enhanced selection for super-fine wool sheep through gene-assisted selection or targeted gene manipulation in the future.
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Affiliation(s)
- Yaojing Yue
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Tingting Guo
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Jianbin Liu
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Jian Guo
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Chao Yuan
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Ruilin Feng
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Chune Niu
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Xiaoping Sun
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
| | - Bohui Yang
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Jiangouyan Street, Lanzhou, China
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ZHANG ZHONGKUI, YANG YONG, BAI SHURONG, ZHANG GUIZHEN, LIU TAIHUA, ZHOU ZHOU, WANG CHUNMEI, TANG LIJUN, WANG JUN, HE SIXIAN. Screening for key genes associated with atopic dermatitis with DNA microarrays. Mol Med Rep 2014; 9:1049-55. [DOI: 10.3892/mmr.2014.1908] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 12/16/2013] [Indexed: 11/05/2022] Open
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14
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Carregaro F, Stefanini ACB, Henrique T, Tajara EH. Study of small proline-rich proteins (SPRRs) in health and disease: a review of the literature. Arch Dermatol Res 2013; 305:857-66. [DOI: 10.1007/s00403-013-1415-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 09/11/2013] [Accepted: 09/16/2013] [Indexed: 12/26/2022]
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15
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Kypriotou M, Boéchat C, Huber M, Hohl D. Spontaneous atopic dermatitis-like symptoms in a/a ma ft/ma ft/J flaky tail mice appear early after birth. PLoS One 2013; 8:e67869. [PMID: 23844115 PMCID: PMC3700905 DOI: 10.1371/journal.pone.0067869] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 05/21/2013] [Indexed: 01/27/2023] Open
Abstract
Loss-of-function mutations in human profilaggrin gene have been identified as the cause of ichthyosis vulgaris (IV), and as a major predisposition factor for atopic dermatitis (AD). Similarly, flaky tail (a/a ma ft/ma ft/J) mice were described as a model for IV, and shown to be predisposed to eczema. The aim of this study was to correlate the flaky tail mouse phenotype with human IV and AD, in order to dissect early molecular events leading to atopic dermatitis in mice and men, suffering from filaggrin deficiency. Thus, 5-days old flaky tail pups were analyzed histologically, expression of cytokines was measured in skin and signaling pathways were investigated by protein analysis. Human biopsies of IV and AD patients were analyzed histologically and by real time PCR assays. Our data show acanthosis and hyperproliferation in flaky tail epidermis, associated with increased IL1β and thymic stromal lymphopoietin (TSLP) expression, and Th2-polarization. Consequently, NFκB and Stat pathways were activated, and IL6 mRNA levels were increased. Further, quantitative analysis of late epidermal differentiation markers revealed increased Small proline-rich protein 2A (Sprr2a) synthesis. Th2-polarization and Sprr2a increase may result from high TSLP expression, as shown after analysis of 5-days old K14-TSLP tg mouse skin biopsies. Our findings in the flaky tail mouse correlate with data obtained from patient biopsies of AD, but not IV. We propose that proinflammatory cytokines are responsible for acanthosis in flaky tail epidermis, and together with the Th2-derived cytokines lead to morphological changes. Accordingly, the a/a ma ft/ma ft/J mouse model can be used as an appropriate model to study early AD onset associated with profilaggrin deficiency.
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Affiliation(s)
- Magdalini Kypriotou
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
| | - Cloé Boéchat
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
| | - Marcel Huber
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
| | - Daniel Hohl
- Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland
- * E-mail:
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16
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Regal JF, Greene AL, Regal RR. Mechanisms of occupational asthma: Not all allergens are equal. Environ Health Prev Med 2012; 12:165-71. [PMID: 21432060 DOI: 10.1007/bf02897986] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2007] [Accepted: 03/09/2007] [Indexed: 01/17/2023] Open
Abstract
Asthma is a heterogeneous lung disorder characterized by airway obstruction, inflammation and eosinophil infiltration into the lung. Both genetics and environmental factors influence the expression of asthma, and not all asthma is the result of a specific immune response to allergen. Numerous asthma phenotypes have been described, including occupational asthma, and therapeutic strategies for asthma control are similar regardless of phenotype. We hypothesized that mechanistic pathways leading to asthma symptoms in the effector phase of the disorder differ with the inciting allergen. Since route of allergen exposure can influence mechanistic pathways, mice were sensitized by identical routes with a high molecular weight occupational allergen ovalbumin and a low molecular weight occupational allergen trimellitic anhydride (TMA). Different statistical methods with varying selection criteria resulted in identification of similar candidate genes. Array data are intended to provide candidate genes for hypothesis generation and further experimentation. Continued studies focused on genes showing minimal changes in the TMA-induced model but with clear up-regulation in the ovalbumin model. Two of these genes, arginase 1 and eotaxin 1 are the focus of continuing investigations in mouse models of asthma regarding differences in mechanistic pathways depending on the allergen. Microarray data from the ovalbumin and TMA model of asthma were also compared to previous data usingAspergillus as allergen to identify putative asthma 'signature genes', i.e. genes up-regulated with all 3 allergens. Array studies provide candidate genes to identify common mechanistic pathways in the effector phase, as well as mechanistic pathways unique to individual allergens.
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Affiliation(s)
- Jean F Regal
- Department of Biochemistry & Molecular Biology, University of Minnesota Medical School Duluth, 1035 University Drive, 55812, Duluth, MN, USA,
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Leclerc D, Cao Y, Deng L, Mikael LG, Wu Q, Rozen R. Differential gene expression and methylation in the retinoid/PPARA pathway and of tumor suppressors may modify intestinal tumorigenesis induced by low folate in mice. Mol Nutr Food Res 2012; 57:686-97. [PMID: 23001810 DOI: 10.1002/mnfr.201200212] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 06/20/2012] [Accepted: 06/25/2012] [Indexed: 01/01/2023]
Abstract
SCOPE Inadequate folate intake increases risk for colorectal cancer. We previously showed that low-folate diets induced intestinal tumors in BALB/c mice, but not in C57BL/6 mice. We suggested that DNA damage, altered methylation, and reduced apoptosis could contribute to tumorigenesis in this model. METHODS AND RESULTS To identify genes involved in tumorigenesis, we compared gene expression profiles in preneoplastic intestine of BALB/c and C57BL/6 mice-fed low folate. We identified 74 upregulated and 90 downregulated genes in BALB/c compared to C57BL/6 mice. We validated decreased expression of Bcmo1 and increased expression of Aldh1a, which would be expected to upregulate the peroxisome proliferator-activated receptor alpha (PPARA) pathway, and confirmed the expected upregulation of several Ppara downstream genes. We verified, in BALB/c mice, reduced expression of Sprr2a, a gene that increases resistance to oxidative damage, and of two oncosuppressors (Bmp5 and Arntl). Low folate increased Ppara and Aldh1a1 expression, and decreased Bcmo1, Sprr2a, and Bmp5 expression in BALB/c, compared to BALB/c on control diets. Bcmo1, Ppara, and Bmp5 showed differential DNA methylation related to strain, diet, and/or Mthfr genotype. CONCLUSION Disturbed regulation of the retinoid/PPARA pathway, which influences oxidative damage, and altered expression of tumor suppressors may contribute to intestinal tumorigenesis induced by low-folate intake.
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Affiliation(s)
- Daniel Leclerc
- Department of Human Genetics, Montreal Children's Hospital Research Institute, McGill University, Montreal, Canada
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18
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Graft versus host disease in the bone marrow, liver and thymus humanized mouse model. PLoS One 2012; 7:e44664. [PMID: 22957096 PMCID: PMC3434179 DOI: 10.1371/journal.pone.0044664] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 08/06/2012] [Indexed: 02/06/2023] Open
Abstract
Mice bearing a “humanized” immune system are valuable tools to experimentally manipulate human cells in vivo and facilitate disease models not normally possible in laboratory animals. Here we describe a form of GVHD that develops in NOD/SCID mice reconstituted with human fetal bone marrow, liver and thymus (NS BLT mice). The skin, lungs, gastrointestinal tract and parotid glands are affected with progressive inflammation and sclerosis. Although all mice showed involvement of at least one organ site, the incidence of overt clinical disease was approximately 35% by 22 weeks after reconstitution. The use of hosts lacking the IL2 common gamma chain (NOD/SCID/γc−/−) delayed the onset of disease, but ultimately did not affect incidence. Genetic analysis revealed that particular donor HLA class I alleles influenced the risk for the development of GVHD. At a cellular level, GVHD is associated with the infiltration of human CD4+ T cells into the skin and a shift towards Th1 cytokine production. GVHD also induced a mixed M1/M2 polarization phenotype in a dermal murine CD11b+, MHC class II+ macrophage population. The presence of xenogenic GVHD in BLT mice both presents a major obstacle in the use of humanized mice and an opportunity to conduct preclinical studies on GVHD in a humanized model.
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19
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Simons JL, Vintiner SK. Efficacy of Several Candidate Protein Biomarkers in the Differentiation of Vaginal from Buccal Epithelial Cells*. J Forensic Sci 2012; 57:1585-90. [DOI: 10.1111/j.1556-4029.2012.02158.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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20
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Epstein TG, LeMasters GK, Bernstein DI, Ericksen MB, Martin LJ, Ryan PH, Biagini Myers JM, Butsch Kovacic MS, Lindsey MA, He H, Reponen T, Villareal MS, Lockey JE, Bernstein CK, Khurana Hershey GK. Genetic variation in small proline rich protein 2B as a predictor for asthma among children with eczema. Ann Allergy Asthma Immunol 2012; 108:145-50. [PMID: 22374195 DOI: 10.1016/j.anai.2012.01.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 12/06/2011] [Accepted: 01/10/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Small proline rich protein 2B (SPRR2B) is a skin and lung epithelial protein associated with allergic inflammation in mice that has not been evaluated in human atopic diseases. OBJECTIVE To determine whether single-nucleotide polymorphisms (SNPs) in SPRR2B are associated with childhood eczema and with the phenotype of childhood eczema combined with asthma. METHODS Genotyping for SPRR2B and filaggrin (FLG) was performed in 2 independent populations: the Cincinnati Childhood Allergy & Air Pollution Study (CCAAPS; N = 762; birth-age, 4 years) and the Greater Cincinnati Pediatric Clinical Repository (GCPCR; N = 1152; ages 5-10 years). Eczema and eczema plus asthma were clinical outcomes based on parental report and clinician's diagnosis. Genetic analyses were restricted to whites and adjusted for sex in both cohorts and adjusted for environmental covariates in CCAAPS. RESULTS Variants in SPRR2B were not significantly associated with eczema in either cohort after Bonferroni adjustment. Children from both cohorts with the CC genotype of the SPRR2B rs6693927 SNP were at 4 times the risk for eczema plus asthma (adjusted odds ratio, 4.1; 95% confidence interval, 1.5-10.9; P = .005 in CCAAPS; and adjusted odds ratio, 4.0; 95% confidence interval, 1.8-9.1; P < .001 in the GCPCR), however. SNPs in SPRR2B were not in strong linkage disequilibrium with the R501X and del2282 FLG mutations, and these findings were independent of FLG. CONCLUSIONS An SNP in SPRR2B was predictive of asthma among white children with eczema from 2 independent populations. SPRR2B polymorphisms may serve as important predictive markers for the combined eczema plus asthma phenotype.
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Affiliation(s)
- Tolly G Epstein
- Department of Medicine, Division of Immunology, Allergy, and Rheumatology, University of Cincinnati, Cincinnati, Ohio 45229, USA
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21
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Greenblatt MB, Sargent JL, Farina G, Tsang K, Lafyatis R, Glimcher LH, Whitfield ML, Aliprantis AO. Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:1080-1094. [PMID: 22245215 DOI: 10.1016/j.ajpath.2011.11.024] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 11/03/2011] [Accepted: 11/17/2011] [Indexed: 01/13/2023]
Abstract
Development of personalized treatment regimens is hampered by lack of insight into how individual animal models reflect subsets of human disease, and autoimmune and inflammatory conditions have proven resistant to such efforts. Scleroderma is a lethal autoimmune disease characterized by fibrosis, with no effective therapy. Comparative gene expression profiling showed that murine sclerodermatous graft-versus-host disease (sclGVHD) approximates an inflammatory subset of scleroderma estimated at 17% to 36% of patients analyzed with diffuse, 28% with limited, and 100% with localized scleroderma. Both sclGVHD and the inflammatory subset demonstrated IL-13 cytokine pathway activation. Host dermal myeloid cells and graft T cells were identified as sources of IL-13 in the model, and genetic deficiency of either IL-13 or IL-4Rα, an IL-13 signal transducer, protected the host from disease. To identify therapeutic targets, we explored the intersection of genes coordinately up-regulated in sclGVHD, the human inflammatory subset, and IL-13-treated fibroblasts; we identified chemokine CCL2 as a potential target. Treatment with anti-CCL2 antibodies prevented sclGVHD. Last, we showed that IL-13 pathway activation in scleroderma patients correlated with clinical skin scores, a marker of disease severity. Thus, an inflammatory subset of scleroderma is driven by IL-13 and may benefit from IL-13 or CCL2 blockade. This approach serves as a model for personalized translational medicine, in which well-characterized animal models are matched to molecularly stratified patient subsets.
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Affiliation(s)
- Matthew B Greenblatt
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
| | - Jennifer L Sargent
- Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire
| | - Giuseppina Farina
- Division of Rheumatology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Kelly Tsang
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
| | - Robert Lafyatis
- Division of Rheumatology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Laurie H Glimcher
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts; Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Ragon Institute, Massachusetts General Hospital, Harvard University, and Massachusetts Institute of Technology, Boston, Massachusetts
| | | | - Antonios O Aliprantis
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts; Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Schroer KT, Gibson AM, Sivaprasad U, Bass SA, Ericksen MB, Wills-Karp M, Lecras T, Fitzpatrick AM, Brown LAS, Stringer KF, Hershey GKK. Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress. J Allergy Clin Immunol 2011; 128:539-48. [PMID: 21570714 DOI: 10.1016/j.jaci.2011.04.018] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 04/12/2011] [Accepted: 04/14/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND Glutathione S-transferase pi (GSTPi) is the predominant redox regulator in the lung. Although evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive. OBJECTIVES We sought to determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis. METHODS We elucidated the regulation of GSTPi in children with asthma and used murine models of asthma to determine the role of GSTPi in redox homeostasis. RESULTS Our findings demonstrate that GSTPi transcript levels are markedly downregulated in allergen- and IL-13-treated murine models of asthma through signal transducer and activator of transcription 6-dependent and independent pathways. Nuclear factor erythroid 2-related factor 2 was also downregulated in these models. The decrease in GSTPi expression was associated with decreased total glutathione S-transferase activity in the lungs of mice. Examination of cystine intermediates uncovered a functional role for GSTPi in regulating cysteine oxidation, whereby GSTPi-deficient mice exhibited increased oxidative stress (increase in percentage cystine) compared with wild-type mice after allergen challenge. GSTPi expression was similarly downregulated in children with asthma. CONCLUSIONS These data collectively suggest that downregulation of GSTPi after allergen challenge might contribute to the asthma phenotype because of disruption of redox homeostasis and increased oxidative stress. Furthermore, GSTPi might be an important therapeutic target for asthma, and evaluation of GSTPi expression might prove beneficial in identifying patients who would benefit from therapy targeting this pathway.
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Affiliation(s)
- Kathy T Schroer
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
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Burgess STG, Frew D, Nunn F, Watkins CA, McNeilly TN, Nisbet AJ, Huntley JF. Transcriptomic analysis of the temporal host response to skin infestation with the ectoparasitic mite Psoroptes ovis. BMC Genomics 2010; 11:624. [PMID: 21067579 PMCID: PMC3091762 DOI: 10.1186/1471-2164-11-624] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Accepted: 11/10/2010] [Indexed: 11/20/2022] Open
Abstract
Background Infestation of ovine skin with the ectoparasitic mite Psoroptes ovis results in a rapid cutaneous immune response, leading to the crusted skin lesions characteristic of sheep scab. Little is known regarding the mechanisms by which such a profound inflammatory response is instigated and to identify novel vaccine and drug targets a better understanding of the host-parasite relationship is essential. The main objective of this study was to perform a combined network and pathway analysis of the in vivo skin response to infestation with P. ovis to gain a clearer understanding of the mechanisms and signalling pathways involved. Results Infestation with P. ovis resulted in differential expression of 1,552 genes over a 24 hour time course. Clustering by peak gene expression enabled classification of genes into temporally related groupings. Network and pathway analysis of clusters identified key signalling pathways involved in the host response to infestation. The analysis implicated a number of genes with roles in allergy and inflammation, including pro-inflammatory cytokines (IL1A, IL1B, IL6, IL8 and TNF) and factors involved in immune cell activation and recruitment (SELE, SELL, SELP, ICAM1, CSF2, CSF3, CCL2 and CXCL2). The analysis also highlighted the influence of the transcription factors NF-kB and AP-1 in the early pro-inflammatory response, and demonstrated a bias towards a Th2 type immune response. Conclusions This study has provided novel insights into the signalling mechanisms leading to the development of a pro-inflammatory response in sheep scab, whilst providing crucial information regarding the nature of mite factors that may trigger this response. It has enabled the elucidation of the temporal patterns by which the immune system is regulated following exposure to P. ovis, providing novel insights into the mechanisms underlying lesion development. This study has improved our existing knowledge of the host response to P. ovis, including the identification of key parallels between sheep scab and other inflammatory skin disorders and the identification of potential targets for disease control.
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Affiliation(s)
- Stewart T G Burgess
- Moredun Research Institute, Pentlands Science Park, Bush Loan, Edinburgh, Midlothian, EH26 0PZ, Scotland, UK.
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Mattila P, Renkonen J, Toppila-Salmi S, Parviainen V, Joenväärä S, Alff-Tuomala S, Nicorici D, Renkonen R. Time-series nasal epithelial transcriptomics during natural pollen exposure in healthy subjects and allergic patients. Allergy 2010; 65:175-83. [PMID: 19804444 DOI: 10.1111/j.1398-9995.2009.02181.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND The role of epithelium has recently awakened interest in the studies of type I hypersensitivity. OBJECTIVE We analysed the nasal transcriptomics epithelial response to natural birch pollen exposure in a time series manner. METHODS Human nasal epithelial cell swabs were collected from birch pollen allergic patients and healthy controls in winter season. In addition, four specimens at weekly intervals were collected from the same subjects during natural birch pollen exposure in spring and transcriptomic analyses were performed. RESULTS The nasal epithelium of healthy subjects responded vigorously to allergen exposure. The immune response was a dominating category of this response. Notably, the healthy subjects did not display any clinical symptoms regardless of this response detected by transcriptomic analysis. Concomitantly, the epithelium of allergic subjects responded also, but with a different set of responders. In allergic patients the regulation of dyneins, the molecular motors of intracellular transport dominated. This further supports our previous hypothesis that the birch pollen exposure results in an active uptake of allergen into the epithelium only in allergic subjects but not in healthy controls. CONCLUSION We showed that birch pollen allergen causes a defence response in healthy subjects, but not in allergic subjects. Instead, allergic patients actively transport pollen allergen through the epithelium to tissue mast cells. Our study showed that new hypotheses can arise from the application of discovery driven methodologies. To understand complex multifactorial diseases, such as type I hypersensitivity, this kind of hypotheses might be worth further analyses.
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Tachdjian R, Mathias C, Al Khatib S, Bryce PJ, Kim HS, Blaeser F, O'Connor BD, Rzymkiewicz D, Chen A, Holtzman MJ, Hershey GK, Garn H, Harb H, Renz H, Oettgen HC, Chatila TA. Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. ACTA ACUST UNITED AC 2009; 206:2191-204. [PMID: 19770271 PMCID: PMC2757875 DOI: 10.1084/jem.20091480] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling.
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Affiliation(s)
- Raffi Tachdjian
- Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Tölgyesi G, Molnár V, Semsei AF, Kiszel P, Ungvári I, Pócza P, Wiener Z, Komlósi ZI, Kunos L, Gálffy G, Losonczy G, Seres I, Falus A, Szalai C. Gene expression profiling of experimental asthma reveals a possible role of paraoxonase-1 in the disease. Int Immunol 2009; 21:967-75. [PMID: 19556304 DOI: 10.1093/intimm/dxp063] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
In this study, we aimed to identify novel genes involved in experimental and human asthma, importance of which has not yet been recognized. In an ovalbumin-induced murine model of asthma, we applied microarray gene expression analysis at different time points after allergen challenges. Advanced statistical methods were used to relate gene expression changes to cellular processes and to integrate our results into multiple levels of information available in public databases. At 4 h after the first allergen challenge, gene expression pattern reflected mainly an acute, but non-atopic, inflammatory response and strong chemotactic activity. At 24 h after the third allergen challenge, gene set enrichment analysis revealed significant over-representation of gene sets corresponding to T(h)2-type inflammation models. Among the top down-regulated transcripts, an anti-oxidant enzyme, paraoxonase-1 (PON1), was identified. In human asthmatic patients, we found that serum PON1 activity was reduced at exacerbation, but increased parallel with improving asthma symptoms. PON1 gene polymorphisms did not influence the susceptibility to the disease. Our observations suggest that an altered PON1 activity might be involved in the pathogenesis of asthma, and serum PON1 level might be used for following up the effect of therapy.
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Affiliation(s)
- Gergely Tölgyesi
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
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Lee HJ, Pazin DE, Kahlon RS, Correa SM, Albrecht KH. Novel markers of early ovarian pre-granulosa cells are expressed in an Sry-like pattern. Dev Dyn 2009; 238:812-25. [PMID: 19301398 DOI: 10.1002/dvdy.21902] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mammalian gonad differentiation involves sexually dimorphic cell-fate decisions within the bipotential gonadal primordia. Testis differentiation is initiated by a center-to-poles wave of Sry expression that induces supporting cell precursors (SCPs) to become Sertoli rather than granulosa cells. The initiation of ovary differentiation is less well understood. We identified two novel SCP markers, 1700106J16Rik and Sprr2d, whose expression is ovary-biased during early gonad development, and altered in Wnt4, Sf1, Wt1, and Fog2 mutant gonads. In XX and XY gonads, both genes were up-regulated at approximately E11 in a center-to-poles wave, and then rapidly down-regulated in XY gonads in a center-to-poles wave, which is reminiscent of Sry expression in XY gonads. Our data suggest that 1700106J16Rik and Sprr2d may have important roles in early gonad development, and are consistent with the hypothesis that ovarian SCP differentiation occurs in a center-to-poles wave with similar timing to that of testicular SCP differentiation.
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Affiliation(s)
- Hyunjoo J Lee
- Department of Medicine, Genetics Program, Boston University School of Medicine, Boston, Massachusetts 02118, USA
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Lewis CC, Aronow B, Hutton J, Santeliz J, Dienger K, Herman N, Finkelman FD, Wills-Karp M. Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung. J Allergy Clin Immunol 2009; 123:795-804.e8. [PMID: 19249085 DOI: 10.1016/j.jaci.2009.01.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Revised: 12/04/2008] [Accepted: 01/09/2009] [Indexed: 01/13/2023]
Abstract
BACKGROUND Allergic asthma results from inappropriate T(H)2-mediated inflammation. Both IL-4 and IL-13 contribute to asthma pathogenesis, but IL-4 predominantly drives T(H)2 induction, whereas IL-13 is necessary and sufficient for allergen-induced airway hyperresponsiveness and goblet cell hyperplasia. Although these 2 cytokines share signaling components, the molecular mechanisms by which they mediate different phases of the allergic asthmatic response remain elusive. OBJECTIVE We sought to clarify the role or roles of IL-4 and IL-13 in asthma-pathogenesis. METHODS We used DNA Affymetrix microarrays to profile pulmonary gene expression in BALB/c mice inoculated intratracheally with ragweed pollen, house dust mite, IL-4, IL-13, or both cytokines. IL-13 dependence was confirmed by comparing pulmonary gene expression in house dust mite-inoculated wild-type and IL-13 knockout mice. RESULTS A signature gene expression profile consisting of 23 genes was commonly induced by means of inoculation with house dust mite, ragweed pollen, or IL-4 plus IL-13. Although rIL-4 and rIL-13 treatment induced an overlapping set of genes, IL-4 uniquely induced 21 genes, half of which were interferon response genes and half of which were genes important in immunoregulation. IL-13 uniquely induced 8 genes, most of which encode proteins produced by epithelial cells. CONCLUSIONS IL-4 and IL-13 together account for most allergen-induced pulmonary genes. Selective IL-4 induction of IFN-gamma response genes and other genes that might negatively regulate allergic inflammation could partially explain the greater importance of IL-13 in the effector phase of allergic airway disease.
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Affiliation(s)
- Christina C Lewis
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229, USA
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29
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Zheng L, Zhou Z, Lin L, Alber S, Watkins S, Kaminski N, Choi AMK, Morse D. Carbon monoxide modulates alpha-smooth muscle actin and small proline rich-1a expression in fibrosis. Am J Respir Cell Mol Biol 2008; 41:85-92. [PMID: 19097987 DOI: 10.1165/rcmb.2007-0401oc] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Carbon monoxide (CO) is a biologically active molecule produced in the body by the stress-inducible enzyme, heme oxygenase. We have previously shown that CO suppresses fibrosis in a murine bleomycin model. To investigate the mechanisms by which CO opposes fibrogenesis, we performed gene expression profiling of fibroblasts treated with transforming growth factor-beta(1) and CO. The most highly differentially expressed categories of genes included those related to muscular system development and the small proline-rich family of proteins. We confirmed in vitro, and in an in vivo bleomycin model of lung fibrosis, that CO suppresses alpha-smooth muscle actin expression and enhances small proline-rich protein-1a expression. We further show that these effects of CO depend upon signaling via the extracellular signal-regulated kinase pathway. Our results demonstrate novel transcriptional targets for CO and further elucidate the mechanism by which CO suppresses fibrosis.
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Affiliation(s)
- Liang Zheng
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Kim Y, Lee YS, Hahn JH, Choe J, Kwon HJ, Ro JY, Jeoung D. Hyaluronic acid targets CD44 and inhibits FcepsilonRI signaling involving PKCdelta, Rac1, ROS, and MAPK to exert anti-allergic effect. Mol Immunol 2008; 45:2537-47. [PMID: 18289679 DOI: 10.1016/j.molimm.2008.01.008] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2007] [Revised: 01/05/2008] [Accepted: 01/08/2008] [Indexed: 01/24/2023]
Abstract
Effects of hyaluronic acid (HA) on allergic inflammation were investigated. HA exerted negative effects on beta-hexoaminidase secretion and histamine release in antigen-stimulated rat basophilic leukemia (RBL2H3) cells. HA inhibited interaction between IgE and FcepsilonRI and between FcepsilonRI and PKCdelta. HA inhibited CD44 interaction with PKCalpha, indicating that HA targets CD44. PKCalpha and -delta were responsible for increased Rac1 activity and expression of p47(phox), p67(phox). HA inhibited phosphorylation of PKCalpha and -delta. Rac1 was responsible for increased ROS, and NADPH oxidase was the main source for ROS. The inhibition of PKC prevented antigen from increasing phosphorylation of ERK and p38 MAPK. ERK, p38 MAPK, and ROS, were responsible for secretion of beta-hexosaminidase, histamine release, and induction of chemokines. HA suppressed induction of chemokines, such as MIP-2 and Sprr-2a. CD44 mediated effect of antigen on phosphorylation of ERK, p38MAPK, ROS production, secretion of beta-hexosaminidase, and histamine release. GPCR did not mediate allergic function of antigen or affect anti-allergic function of HA. In vivo anti-allergic effect of HA was investigated using Nc/Nga mice model of DNFB-induced atopic dermatitis. HA reduced skin lesions in Nc/Nga mice treated with DNFB, decreased expression levels of MIP-2, Sprr-2a, and serum IgE level. In conclusion, hyaluronic acid exerts negative effect on allergic inflammation by targeting CD44 and inhibiting FcepsilonRI signaling.
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Affiliation(s)
- Youngmi Kim
- College of Natural Sciences, Kangwon National University, Chunchon 200-701, Republic of Korea
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31
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Li S, Nikulina K, DeVoss J, Wu AJ, Strauss EC, Anderson MS, McNamara NA. Small proline-rich protein 1B (SPRR1B) is a biomarker for squamous metaplasia in dry eye disease. Invest Ophthalmol Vis Sci 2008; 49:34-41. [PMID: 18172072 DOI: 10.1167/iovs.07-0685] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
PURPOSE Squamous metaplasia occurs in ocular surface diseases like Sjögren's syndrome (SS). It is a phenotypic change whereby epithelial cells initiate synthesis of squamous cell-specific proteins such as small proline-rich protein 1B (SPRR1B) that result in pathologic keratin formation on the ocular surface. The authors hypothesized that inflammation is a key inducer of pathologic keratinization and that SPRR1B represents an analytical biomarker for the study of the molecular mechanisms. METHODS Real-time quantitative RT-PCR and immunohistochemistry were used to examine SPRR1B mRNA and protein in two different mouse models of dry eye and patients with SS. Adoptive transfer of mature lymphocytes from mice lacking the autoimmune regulator (aire) gene was performed to examine the role of inflammation as an inducer of squamous metaplasia. SPRR1B expression in response to several cytokines was examined in vitro, whereas the expression of cytokines IL1beta and IFNgamma was quantified in ocular tissues of aire-deficient mice and patients with SS. RESULTS SPRR1B was increased across the ocular surface of mice with both desiccating stress and autoimmune-mediated, aqueous-deficient dry eye and in patients with SS. Adoptive transfer of CD4(+) T cells from aire-deficient mice to immunodeficient recipients caused advanced ocular surface keratinization. IL1alpha, IL1beta, IL6, IFNgamma, and TNFalpha induced SPRR1B expression in vitro and the local expression of IL1beta and IFNgamma was elevated in ocular tissues of patients with SS and aire-deficient mice. CONCLUSIONS SPRR1B is a valid biomarker for the study of the molecular mechanisms of squamous metaplasia. There is a definitive link between inflammation and squamous metaplasia in autoimmune-mediated dry eye disease, with IL1beta and IFNgamma likely acting as key participants.
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Affiliation(s)
- Shimin Li
- Francis I. Proctor Foundation, University of California-San Francisco, 513 Parnassus, San Francisco, CA 94143, USA
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Small proline-rich proteins (SPRR) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial-mesenchymal transition (EMT) in cholangiocytes. J Hepatol 2008; 48:276-88. [PMID: 18155796 PMCID: PMC2263141 DOI: 10.1016/j.jhep.2007.09.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2007] [Revised: 09/04/2007] [Accepted: 09/05/2007] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS Deficient biliary epithelial cell (BEC) expression of small proline-rich protein (SPRR) 2A in IL-6(-/-) mice is associated with defective biliary barrier function after bile duct ligation. And numerous gene array expression studies show SPRR2A to commonly be among the most highly up-regulated genes in many non-squamous, stressed and remodeling barrier epithelia. Since the function of SPRR in these circumstances is unknown, we tested the exploratory hypothesis that BEC SPRR2A expression contributes to BEC barrier function and wound repair. METHODS The effect of SPRR2A expression was studied in primary mouse BEC cultures; in a BEC cell line after forced overexpression of SPRR2A; and in human livers removed at the time of liver transplantation. RESULTS Forced SPRR2A overexpression showed that it functions as a SH3 domain ligand that increases resistance to oxidative injury and promotes wound restitution by enhancing migration and acquisition of mesenchymal characteristics. Low confluency non-neoplastic mouse BEC cultures show a phenotype similar to the stable transfectants, as did spindle-shaped BEC participating in atypical ductular reactions in primary biliary cirrhosis. CONCLUSIONS These observations suggest that SPRR2A-related BEC barrier modifications represent a novel, but widely utilized and evolutionarily conserved, response to stress that is worthy of further study.
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Novershtern N, Itzhaki Z, Manor O, Friedman N, Kaminski N. A functional and regulatory map of asthma. Am J Respir Cell Mol Biol 2007; 38:324-36. [PMID: 17921359 DOI: 10.1165/rcmb.2007-0151oc] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The prevalence and morbidity of asthma, a chronic inflammatory airway disease, is increasing. Animal models provide a meaningful but limited view of the mechanisms of asthma in humans. A systems-level view of asthma that integrates multiple levels of molecular and functional information is needed. For this, we compiled a gene expression compendium from five publicly available mouse microarray datasets and a gene knowledge base of 4,305 gene annotation sets. Using this collection we generated a high-level map of the functional themes that characterize animal models of asthma, dominated by innate and adaptive immune response. We used Module Networks analysis to identify co-regulated gene modules. The resulting modules reflect four distinct responses to treatment, including early response, general induction, repression, and IL-13-dependent response. One module with a persistent induction in response to treatment is mainly composed of genes with suggested roles in asthma, suggesting a similar role for other module members. Analysis of IL-13-dependent response using protein interaction networks highlights a role for TGF-beta1 as a key regulator of asthma. Our analysis demonstrates the discovery potential of systems-level approaches and provides a framework for applying such approaches to asthma.
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Affiliation(s)
- Noa Novershtern
- School of Computer Science and Engineering, Faculty of Medicine, The Hebrew University, Jerusalem
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Hoffjan S, Stemmler S. On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis. Br J Dermatol 2007; 157:441-9. [PMID: 17573887 DOI: 10.1111/j.1365-2133.2007.07999.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Undisturbed epidermal differentiation is crucial for an intact skin barrier function. The epidermal differentiation complex (EDC) is a cluster of genes on chromosome 1q21 encoding proteins that fulfil important functions in terminal differentiation in the human epidermis, including filaggrin, loricrin, S100 proteins and others. Recently, evidence emerged that variation within EDC genes plays an important role in the pathogenesis of three common skin disorders, ichthyosis vulgaris, atopic dermatitis (AD) and psoriasis. Two loss-of-function mutations in the filaggrin (FLG) gene, R501X and 2282del4, were identified as causative for ichthyosis vulgaris in 15 affected European families, and the mode of inheritance was found to be semidominant. As ichthyosis vulgaris and AD often occur concomitantly in affected individuals, these two mutations were subsequently investigated in AD patients and found to be strongly associated with the disease. Following this first report, seven replication studies have been performed that all confirm an association of these two mutations with AD (or AD subtypes) in several European cohorts. Additionally, two unique loss-of-function mutations in the FLG gene were identified in Japanese ichthyosis vulgaris families and found to be associated with AD in a Japanese cohort. Thus, the FLG mutations are among the most consistently replicated associations for AD. Additionally, linkage analysis has suggested that variation within the EDC might also predispose for psoriasis but the exact susceptibility variation(s) have not yet been elucidated. Taken together, these findings convincingly demonstrate the important role of barrier dysfunction in various common skin disorders.
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Affiliation(s)
- S Hoffjan
- Department of Human Genetics, Ruhr-University, Universitätsstrasse 150, 44801 Bochum, Germany.
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Sharma M, Mehla K, Batra J, Ghosh B. Association of a chromosome 1q21 locus in close proximity to a late cornified envelope-like proline-rich 1 (LELP1) gene with total serum IgE levels. J Hum Genet 2007; 52:378-383. [PMID: 17387579 DOI: 10.1007/s10038-007-0118-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2006] [Accepted: 01/13/2007] [Indexed: 11/30/2022]
Abstract
The chromosomal region 1q21 has been linked to atopic dermatitis in previous studies. Seven polymorphic repeats were identified in a 0.5 Mb region of chromosome 1q21 encompassing a small proline-rich protein (SPRR) gene cluster, a few S100 gene family members, loricin, and several uncharacterized genes. These repeats were genotyped by fragment length polymorphism analysis in 133 atopic case-parent trios, of which 111 probands had atopic asthma. Our trio-based analysis for association with atopy and atopic asthma revealed no significant allelic or genotypic association for any of the seven loci tested. However, a significant association was observed with locus 5 (3.65 Mb of contig NT_032962) and log(10) serum IgE levels (F = 3.93, P = 0.0008). Results were also replicated in an independent case-control cohort (N (p) = 165, N (c) = 166), where a significant association with log(10) serum IgE levels was observed in the patient group (P = 0.0005). Interestingly, locus 5 is 6.2 kb upstream of a late cornified envelope-like proline-rich 1 (LELP1) gene which encodes a novel small proline rich protein. Further, we have also found a significant association of rs7534334 (tagged SNP from LELP1) SNP with log(10) serum IgE levels in the patient group (P = 0.0029). Thus, our results identify a chromosomal region in close proximity to a novel gene and highlight the need for intense research on LELP1 and other genes close by with respect to atopic disorders.
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Affiliation(s)
- Mamta Sharma
- Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India
| | - Kamiya Mehla
- Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India
| | - Jyotsna Batra
- Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India
| | - Balaram Ghosh
- Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India.
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Reece JJ, Siracusa MC, Scott AL. Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages. Infect Immun 2006; 74:4970-81. [PMID: 16926388 PMCID: PMC1594865 DOI: 10.1128/iai.00687-06] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
While it is well established that infection with the rodent hookworm Nippostrongylus brasiliensis induces a strongly polarized Th2 immune response, little is known about the innate host-parasite interactions that lead to the development of this robust Th2 immunity. We exploited the transient pulmonary phase of N. brasiliensis development to study the innate immune responses induced by this helminth parasite in wild-type (WT) and severe-combined immune deficient (SCID) BALB/c mice. Histological analysis demonstrated that the cellular infiltrates caused by N. brasiliensis transit through the lungs were quickly resolved in WT mice but not in SCID mice. Microarray-based gene expression analysis demonstrated that there was a rapid induction of genes encoding molecules that participate in innate immunity and in repair/remodeling during days 2 to 4 postinfection in the lungs of WT and SCID mice. Of particular note was the rapid upregulation in both WT and SCID mice of the genes encoding YM1, FIZZ1, and Arg1, indicating a role for alternatively activated macrophages (AAMs) in pulmonary innate immunity. Immunohistochemistry revealed that nearly all alveolar macrophages became YM1-producing AAMs as early as day 2 postinfection. While the innate responses induced during the lung phase of N. brasiliensis infection were similar in complexity and magnitude in WT and SCID mice, only mice with functional T cells were capable of maintaining elevated levels of gene expression beyond the innate window of reactivity. The induction of alternatively activated alveolar macrophages could be important for dampening the level of inflammation in the lungs and contribute to the long-term decrease in pulmonary inflammation that has been associated with helminth infections.
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Affiliation(s)
- Joshua J Reece
- W.H. Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA
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Abgueguen E, Toutain B, Bédrine H, Chicault C, Orhant M, Aubry M, Monnier A, Mottier S, Jouan H, Bahram S, Mosser J, Fergelot P. Differential expression of genes related to HFE and iron status in mouse duodenal epithelium. Mamm Genome 2006; 17:430-50. [PMID: 16688533 DOI: 10.1007/s00335-005-0122-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2005] [Accepted: 02/01/2006] [Indexed: 11/29/2022]
Abstract
Iron absorption, distribution, use, and storage are thought to be tightly regulated since altered iron stores may lead to cellular damage and disease. HFE, the hereditary hemochromatosis gene product, is expressed in the crypts of the duodenum, but the molecular mechanism by which it contributes to the inhibition of iron absorption is still unknown. In this study we aimed to identify transcriptional profiles in the duodenal epithelium of Hfe(-/-) mice. We used dedicated microarrays to compare gene expression among the duodenum of Hfe(-/-) mice, induced iron overload mice, and control mice. We found 151 differentially expressed genes and unknown sequences between Hfe(-/-) mice and normal littermates. Gene profiling revealed a gene subset more specific for Hfe inactivation. The functional annotation of upregulated genes highlighted that mucus production and cell maintenance may account for the influence of Hfe on epithelium integrity and luminal iron uptake.
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Affiliation(s)
- Emmanuelle Abgueguen
- CNRS UMR 6061, Université de Rennes1, IFR 140, Faculté de Médecine, CS 34317, 35043 Rennes, France
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Abstract
Antibiotics are increasingly prescribed in the peripartum period, for both maternal and fetal indications. Their effective use undoubtedly reduces the incidence of specific invasive infections in the newborn, such as group B streptococcal septicaemia. However, the total burden of infectious neonatal disease may not be reduced, particularly if broad-spectrum agents are used, as the pattern of infections has been shown to alter to allow dominance of previously uncommon organisms. This area has been relatively understudied, and there are almost no studies of long-term outcome. Recent findings suggest that such long-term data should be sought. First, there is evidence that organisms initially colonising the gut at birth may establish chronic persistence in many children, in contrast to prompt clearance if first encountered in later infancy, childhood or adulthood. Second, there is a rapidly advancing basic scientific data showing that individual members of the gut flora specifically induce gene activation within the host, modulating mucosal and systemic immune function and having an additional impact on metabolic programming. We thus review the published data on the impact of perinatal antibiotic regimens upon composition of the flora and later health outcomes in young children and summarise the recent scientific findings on the potential importance of gut flora composition on immune tolerance and metabolism.
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Abstract
Skin is at the interface between the complex physiology of the body and the external, often hostile, environment, and the semipermeable epidermal barrier prevents both the escape of moisture and the entry of infectious or toxic substances. Newborns with rare congenital barrier defects underscore the skin's essential role in a terrestrial environment and demonstrate the compensatory responses evoked ex utero to reestablish a barrier. Common inflammatory skin disorders such as atopic dermatitis and psoriasis exhibit decreased barrier function, and recent studies suggest that the complex response of epidermal cells to barrier disruption may aggravate, maintain, or even initiate such conditions. Either aiding barrier reestablishment or dampening the epidermal stress response may improve the treatment of these disorders. This Review discusses the molecular regulation of the epidermal barrier as well as causes and potential treatments for defects of barrier formation and proposes that medical management of barrier disruption may positively affect the course of common skin disorders.
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Affiliation(s)
- Julia A Segre
- Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4442, USA.
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40
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Demetris AJ, Lunz JG, Specht S, Nozaki I. Biliary wound healing, ductular reactions, and IL-6/gp130 signaling in the development of liver disease. World J Gastroenterol 2006; 12:3512-22. [PMID: 16773708 PMCID: PMC4087567 DOI: 10.3748/wjg.v12.i22.3512] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Basic and translational wound healing research in the biliary tree lag significantly behind similar studies on the skin and gastrointestinal tract. This is at least partly attributable to lack of easy access to the biliary tract for study. But clinical relevance, more interest in biliary epithelial cell (BEC) pathophysiology, and widespread availability of BEC cultures are factors reversing this trend. In the extra-hepatic biliary tree, ineffectual wound healing, scarring and stricture development are pressing issues. In the smallest intra-hepatic bile ducts either impaired BEC proliferation or an exuberant response can contribute to liver disease. Chronic inflammation and persistent wound healing reactions in large and small bile ducts often lead to liver cancer. General concepts of wound healing as they apply to the biliary tract, importance of cellular processes dependent on IL-6/gp130/STAT3 signaling pathways, unanswered questions, and future directions are discussed.
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Affiliation(s)
- A-J Demetris
- The Thomas E. Starzl Transplantation Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, UPMC-Montefiore E-741, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA.
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Rolph MS, Sisavanh M, Liu SM, Mackay CR. Clues to asthma pathogenesis from microarray expression studies. Pharmacol Ther 2005; 109:284-94. [PMID: 16203040 DOI: 10.1016/j.pharmthera.2005.08.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2005] [Accepted: 08/24/2005] [Indexed: 11/27/2022]
Abstract
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), tissue remodeling, and airflow obstruction. The pathogenesis of asthma is only partly understood, and there is an urgent need for improved therapeutic strategies for this disease. Microarray technology has considerable promise as a tool for discovery of novel asthma therapeutic targets, although the field is still in its infancy. A number of studies have described expression profiles derived from human asthmatic lung tissue, mouse airway tissue, or from key cell types associated with asthma, but to date relatively few studies have exploited these findings to discover new pathways involved in the pathogenesis of asthma. Among the genes to have been identified by array studies and validated by further studies are monokine induced by interferon (IFN)-gamma, fatty acid binding proteins (FABP), and complement factor 5 (C5). Here we provide examples of microarray approaches to the discovery of new molecules associated with asthma. We anticipate that these types of analyses will provide considerable insight into asthma pathogenesis and will provide a wealth of new molecules for downstream analyses such as gene deficient mouse studies, or monoclonal antibody production.
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Affiliation(s)
- Michael S Rolph
- Arthritis and Inflammation Research Program, Garvan Institute for Medical Research, Darlinghurst, Australia.
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Greene AL, Rutherford MS, Regal RR, Flickinger GH, Hendrickson JA, Giulivi C, Mohrman ME, Fraser DG, Regal JF. Arginase activity differs with allergen in the effector phase of ovalbumin- versus trimellitic anhydride-induced asthma. Toxicol Sci 2005; 88:420-33. [PMID: 16141432 PMCID: PMC2978642 DOI: 10.1093/toxsci/kfi311] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Both trimellitic anhydride (TMA), a small molecular weight chemical, and ovalbumin (OVA), a reference protein allergen, cause asthma with eosinophilia. To test the hypothesis that different allergens elicit symptoms of asthma via different effector pathways, gene expression was compared in lungs of Balb/c mice sensitized with either TMA or OVA, followed by intratracheal challenge with TMA conjugated to mouse serum albumin (TMA-MSA) or OVA, respectively. Sensitized animals challenged with mouse serum albumin (MSA) alone were controls. Seventy-two hours after challenge, lung eosinophil peroxidase indicated that both allergens caused the same significant change in eosinophilia. Total RNA was isolated from lung lobes of 6-8 animals in each of four treatment groups and hybridized to Affymetrix U74Av2 GeneChips. False discovery rates (q-values) were calculated from an overall F test to identify candidate genes with differences in expression for the four groups. Using a q-value cutoff of 0.1, 853 probe sets had significantly different expression across the four treatment groups. Of these 853 probe sets, 376 genes had an Experimental/Control ratio of greater than 1.2 or less than 1/1.2 for either OVA- or TMA-treated animals, and 249 of the 376 genes were uniquely up- or down-regulated for OVA or TMA (i.e., differentially expressed with the allergen). qRT-PCR analysis of selected transcripts confirmed the gene expression analysis. Increases in both arginase transcript and enzyme activity were significantly greater in OVA-induced asthma compared to TMA-induced asthma. These data suggest that pathways of arginine metabolism and the importance of nitric oxide may differ in OVA- and TMA-induced asthma.
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Affiliation(s)
- Amy L. Greene
- Department of Biochemistry and Molecular Biology, Medical School Duluth, University of Minnesota, Duluth, Minnesota 55812
| | - Mark S. Rutherford
- Department of Veterinary and Biomedical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108
| | - Ronald R. Regal
- Department of Mathematics and Statistics, College of Science and Engineering, University of Minnesota, Duluth, Minnesota 55812
| | - Gail H. Flickinger
- Department of Veterinary and Biomedical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108
| | - Julie A. Hendrickson
- Department of Veterinary and Biomedical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108
| | - Cecilia Giulivi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616
| | - Margaret E. Mohrman
- Department of Biochemistry and Molecular Biology, Medical School Duluth, University of Minnesota, Duluth, Minnesota 55812
| | - Daniel G. Fraser
- Department of Veterinary and Biomedical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108
| | - Jean F. Regal
- Department of Biochemistry and Molecular Biology, Medical School Duluth, University of Minnesota, Duluth, Minnesota 55812
- To whom correspondence should be addressed at Department of Biochemistry and Molecular Biology, Medical School Duluth, University of Minnesota, Duluth, MN 55812.
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