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Rezazadeh F, Ramos N, Saliganan AD, Al-Hallak N, Chen K, Mohamad B, Wiesend WN, Viola NT. Detection of IL12/23p40 via PET Visualizes Inflammatory Bowel Disease. J Nucl Med 2023; 64:1806-1814. [PMID: 37474270 PMCID: PMC10626378 DOI: 10.2967/jnumed.123.265649] [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: 12/22/2022] [Revised: 06/20/2023] [Indexed: 07/22/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes both Crohn disease and ulcerative colitis, is a relapsing inflammatory disease of the gastrointestinal tract. Long-term chronic inflammatory conditions elevate the patient's risk of colorectal cancer (CRC). Currently, diagnosis requires endoscopy with biopsy. This procedure is invasive and requires a bowel-preparatory regimen, adding to patient burden. Interleukin 12 (IL12) and interleukin 23 (IL23) play key roles in inflammation, especially in the pathogenesis of IBD, and are established therapeutic targets. We propose that imaging of IL12/23 and its p40 subunit in IBD via immuno-PET potentially provides a new noninvasive diagnostic approach. Methods: Our aim was to investigate the potential of immuno-PET to image inflammation in a chemically induced mouse model of colitis using dextran sodium sulfate by targeting IL12/23p40 with a 89Zr-radiolabeled anti-IL12/23p40 antibody. Results: High uptake of the IL12/23p40 immuno-PET agent was exhibited by dextran sodium sulfate-administered mice, and this uptake correlated with increased IL12/23p40 present in the sera. Competitive binding studies confirmed the specificity of the radiotracer for IL12/23p40 in the gastrointestinal tract. Conclusion: These promising results demonstrate the utility of this radiotracer as an imaging biomarker of IBD. Moreover, IL12/23p40 immuno-PET can potentially guide treatment decisions for IBD management.
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Affiliation(s)
- Farzaneh Rezazadeh
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Nicholas Ramos
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Allen-Dexter Saliganan
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Najeeb Al-Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Kang Chen
- Departments of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan
| | - Bashar Mohamad
- Department of Gastroenterology, Wayne State University, Detroit, Michigan; and
| | - Wendy N Wiesend
- Department of Anatomic Pathology, Corewell Health William Beaumont University Hospital, Royal Oak, Michigan
| | - Nerissa T Viola
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan;
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Peters DE, Norris LD, Tenora L, Šnajdr I, Ponti AK, Zhu X, Sakamoto S, Veeravalli V, Pradhan M, Alt J, Thomas AG, Majer P, Rais R, McDonald C, Slusher BS. A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis. Sci Transl Med 2023; 15:eabn7491. [PMID: 37556558 PMCID: PMC10661206 DOI: 10.1126/scitranslmed.abn7491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 07/21/2023] [Indexed: 08/11/2023]
Abstract
There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUCcolon/plasma > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium-induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor-α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.
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Affiliation(s)
- Diane E. Peters
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Lauren D. Norris
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Lukáš Tenora
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 160 00 Prague, Czechia
| | - Ivan Šnajdr
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 160 00 Prague, Czechia
| | - András K. Ponti
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Xiaolei Zhu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shinji Sakamoto
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Vijayabhaskar Veeravalli
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Manisha Pradhan
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jesse Alt
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ajit G. Thomas
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Pavel Majer
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 160 00 Prague, Czechia
| | - Rana Rais
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Christine McDonald
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Barbara S. Slusher
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Little M, Dutta M, Li H, Matson A, Shi X, Mascarinas G, Molla B, Weigel K, Gu H, Mani S, Cui JY. Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice. Acta Pharm Sin B 2022; 12:801-820. [PMID: 35256948 PMCID: PMC8897037 DOI: 10.1016/j.apsb.2021.07.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/29/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.
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Key Words
- BA, bile acid
- BSH, bile salt hydrolase
- Bile acids
- CA, cholic acid
- CAR
- CAR, constitutive androstane receptor
- CDCA, chenodeoxycholic acid
- CITCO, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
- CV, conventional
- CYP, cytochrome P450
- DCA, deoxycholic acid
- EGF, epidermal growth factor
- Feces
- GF, germ free
- GLP-1, glucagon-like peptide-1
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- Gut microbiome
- HDCA, hyodeoxycholic acid
- IBD, inflammatory bowel disease
- IFNγ, interferon-gamma
- IL, interleukin
- IS, internal standards
- Inflammation
- LCA, lithocholic acid
- LC–MS/MS, liquid chromatography–tandem mass spectrometry
- MCA, muricholic acid
- MCP-1, monocyte chemoattractant protein-1
- Mice
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NSAID, non-steroidal anti-inflammatory drug
- Nuclear receptor
- OH, hydroxylated
- OTUs, operational taxonomy units
- PA, indole-3 propionic acid
- PBDEs, polybrominated diphenyl ethers
- PCBs, polychlorinated biphenyls
- PCoA, Principle Coordinate Analysis
- PXR
- PXR, pregnane X receptor
- PiCRUSt, Phylogenetic Investigation of Communities by Reconstruction of Observed States
- QIIME, Quantitative Insights Into Microbial Ecology
- SCFAs, short-chain fatty acids
- SNP, single-nucleotide polymorphism
- SPF, specific-pathogen-free
- T, wild type
- T-, taurine conjugated
- TCPOBOP, 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene, 3,3′,5,5′-Tetrachloro-1,4-bis(pyridyloxy)benzene
- TGR-5, Takeda G-protein-coupled receptor 5
- TLR4, toll-like receptor 4
- TNF, tumor necrosis factor
- UDCA, ursodeoxycholic acid
- YAP, yes-associated protein
- hPXR-TG, humanized PXR transgenic
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Affiliation(s)
- Mallory Little
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Moumita Dutta
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Hao Li
- Department of Medicine, Molecular Pharmacology and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Adam Matson
- University of Connecticut, Hartford, CT 06106, USA
| | - Xiaojian Shi
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA
| | - Gabby Mascarinas
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Bruk Molla
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Kris Weigel
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Haiwei Gu
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA
| | - Sridhar Mani
- Department of Medicine, Molecular Pharmacology and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
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Zhong S, Zhang T, Tang L, Li Y. Cytokines and Chemokines in HBV Infection. Front Mol Biosci 2021; 8:805625. [PMID: 34926586 PMCID: PMC8674621 DOI: 10.3389/fmolb.2021.805625] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 11/15/2021] [Indexed: 12/21/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatic inflammation and damage. The pathogenesis of chronic hepatitis B (CHB) infection is predominantly mediated by persistent intrahepatic immunopathology. With the characterization of unique anatomical and immunological structure, the liver is also deemed an immunological organ, which gives rise to massive cytokines and chemokines under pathogenesis conditions, having significant implications for the progression of HBV infection. The intrahepatic innate immune system is responsible for the formidable source of cytokines and chemokines, with the latter also derived from hepatic parenchymal cells. In addition, systemic cytokines and chemokines are disturbed along with the disease course. Since HBV is a stealth virus, persistent exposure to HBV-related antigens confers to immune exhaustion, whereby regulatory cells are recruited by intrahepatic chemokines and cytokines, including interleukin-10 and transforming growth factor β, are involved in such series of causal events. Although the considerable value of two types of available approved treatment, interferons and nucleos(t)ide analogues, effectively suppress HBV replication, neither of them is sufficient for optimal restoration of the immunological attrition state to win the battle of the functional or virological cure of CHB infection. Notably, cytokines and chemokines play a crucial role in regulating the immune response. They exert effects by directly acting on HBV or indirectly manipulating target immune cells. As such, specific cytokines and chemokines, with a potential possibility to serve as novel immunological interventions, combined with those that target the virus itself, seem to be promising prospects in curative CHB infection. Here, we systematically review the recent literature that elucidates cytokine and chemokine-mediated pathogenesis and immune exhaustion of HBV infection and their dynamics triggered by current mainstream anti-HBV therapy. The predictive value of disease progression or control and the immunotherapies target of specific major cytokines and chemokines in CHB infection will also be delineated.
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Affiliation(s)
- Shihong Zhong
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tianling Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Libo Tang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yongyin Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Simon H, Vartanian V, Wong MH, Nakabeppu Y, Sharma P, Lloyd RS, Sampath H. OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model. PLoS One 2020; 15:e0227501. [PMID: 31935236 PMCID: PMC6959583 DOI: 10.1371/journal.pone.0227501] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 12/19/2019] [Indexed: 02/07/2023] Open
Abstract
OGG1-deficient (Ogg1-/-) animals display increased propensity to age-induced and diet-induced metabolic diseases, including insulin resistance and fatty liver. Since the intestinal microbiome is increasingly understood to play a role in modulating host metabolic responses, we examined gut microbial composition in Ogg1-/- mice subjected to different nutritional challenges. Interestingly, Ogg1-/- mice had a markedly altered intestinal microbiome under both control-fed and hypercaloric diet conditions. Several microbial species that were increased in Ogg1-/- animals were associated with increased energy harvest, consistent with their propensity to high-fat diet induced weight gain. In addition, several pro-inflammatory microbes were increased in Ogg1-/- mice. Consistent with this observation, Ogg1-/- mice were significantly more sensitive to intestinal inflammation induced by acute exposure to dextran sulfate sodium. Taken together, these data indicate that in addition to their proclivity to obesity and metabolic disease, Ogg1-/- mice are prone to colonic inflammation. Further, these data point to alterations in the intestinal microbiome as potential mediators of the metabolic and intestinal inflammatory response in Ogg1-/- mice.
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Affiliation(s)
- Holly Simon
- Division of Environmental and Biomolecular Systems, Institute of Environmental Health, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Vladimir Vartanian
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Fukuoka, Kyushu, Japan
| | - Priyanka Sharma
- Department of Nutritional Sciences, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
- New Jersey Institute for Food, Nutrition, and Health, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
| | - R. Stephen Lloyd
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, United States of America
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Harini Sampath
- Department of Nutritional Sciences, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
- New Jersey Institute for Food, Nutrition, and Health, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
- * E-mail:
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Moschen AR, Tilg H, Raine T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nat Rev Gastroenterol Hepatol 2019; 16:185-196. [PMID: 30478416 DOI: 10.1038/s41575-018-0084-8] [Citation(s) in RCA: 322] [Impact Index Per Article: 53.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn's disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late-phase clinical trials. We review the emerging understanding of the biology of IL-12 and IL-23, as well as that of their major downstream cytokines, including IL-17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology.
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Affiliation(s)
- Alexander R Moschen
- Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria. .,Department of Medicine, Division of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria.
| | - Herbert Tilg
- Department of Medicine, Division of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria
| | - Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Sakkas LI, Mavropoulos A, Perricone C, Bogdanos DP. IL-35: a new immunomodulator in autoimmune rheumatic diseases. Immunol Res 2018; 66:305-312. [DOI: 10.1007/s12026-018-8998-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Vyas SP, Goswami R. Striking the right immunological balance prevents progression of tuberculosis. Inflamm Res 2017; 66:1031-1056. [PMID: 28711989 DOI: 10.1007/s00011-017-1081-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 07/03/2017] [Accepted: 07/07/2017] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Tuberculosis (TB) caused by infection with Mycobacterium tuberculosis (Mtb) is a major burden for human health worldwide. Current standard treatments for TB require prolonged administration of antimycobacterial drugs leading to exaggerated inflammation and tissue damage. This can result in the reactivation of latent TB culminating in TB progression. Thus, there is an unmet need to develop therapies that would shorten the duration of anti-TB treatment and to induce optimal protective immune responses to control the spread of mycobacterial infection with minimal lung pathology. FINDINGS Granulomata is the hallmark structure formed by the organized accumulation of immune cells including macrophages, natural killer cells, dendritic cells, neutrophils, T cells, and B cells to the site of Mtb infection. It safeguards the host by containing Mtb in latent form. However, granulomata can undergo caseation and contribute to the reactivation of latent TB, if the immune responses developed to fight mycobacterial infection are not properly controlled. Thus, an optimal balance between innate and adaptive immune cells might play a vital role in containing mycobacteria in latent form for prolonged periods and prevent the spread of Mtb infection from one individual to another. CONCLUSION Optimal and well-regulated immune responses against Mycobacterium tuberculosis may help to prevent the reactivation of latent TB. Moreover, therapies targeting balanced immune responses could help to improve treatment outcomes among latently infected TB patients and thereby limit the dissemination of mycobacterial infection.
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Affiliation(s)
| | - Ritobrata Goswami
- School of Bio Science, IIT Kharagpur, Kharagpur, West Bengal, 721302, India.
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Significant reduction of peripheral blood interleukin-35 and CD4 +EBI3 + T cells, which are negatively correlated with an increase in the plasma IL-17 and cTnI level, in viral myocarditis patients. Cent Eur J Immunol 2017; 42:91-96. [PMID: 28680336 PMCID: PMC5470605 DOI: 10.5114/ceji.2016.65892] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 01/29/2016] [Indexed: 01/22/2023] Open
Abstract
Introduction Viral myocarditis (VMC) has become an increasingly common heart disease that endangers human health. In the present study, the plasma interleukin-35 (IL-35) level and the percentage of CD4+EBI3+ T cells in VMC patients were detected to investigate the significance of changes in these parameters in the plasma of VMC patients and their association with the disease. Material and methods ELISA was performed to detect the plasma IL-35 level and the percentage of peripheral blood CD4+EBI3+ T cells in 40 VMC patients and in 20 healthy individuals. Moreover, the plasma IL-17 levels in the VMC patients and in the healthy individuals were detected using an ELISA, and the cardiac Troponin-I (cTnI) levels were detected using a chemiluminescent microparticle immunoassay to compare the differences in the groups. Results Plasma IL-35 level and the percentage of CD4+EBI3+ T cells in acute phase VMC patients was lower than that in the healthy control group and the convalescent phase VMC patients. Additionally, the plasma IL-35 level in the VMC patients exhibited a negative correlation with the levels of cTnI and IL-17. The percentage of CD4+EBI3+ T cells also showed a negative correlation with the levels of cTnI and IL-17. Conclusions The plasma IL-35 level and the percentage of CD4+EBI3+ T cells in VMC patients was reduced, and the amount of the decrease was associated with the severity of the disease. These results suggest that IL-35 and CD4+EBI3+ T might play important roles in the progression of VMC and could be used as indictors of the disease.
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10
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Domingo-Gonzalez R, Prince O, Cooper A, Khader SA. Cytokines and Chemokines in Mycobacterium tuberculosis Infection. Microbiol Spectr 2016; 4:10.1128/microbiolspec.TBTB2-0018-2016. [PMID: 27763255 PMCID: PMC5205539 DOI: 10.1128/microbiolspec.tbtb2-0018-2016] [Citation(s) in RCA: 266] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Indexed: 02/06/2023] Open
Abstract
Chemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells into Mycobacterium tuberculosis-infected lungs. Correct mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. An important block to our understanding of TB pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interplay in light of the conditional role these molecules play throughout infection and disease development. Much of the data highlighted in this review appears at first glance to be contradictory, but it is the balance between the cytokines and chemokines that is critical, and the "goldilocks" (not too much and not too little) phenomenon is paramount in any discussion of the role of these molecules in TB. Determination of how the key chemokines/cytokines and their receptors are balanced and how the loss of that balance can promote disease is vital to understanding TB pathogenesis and to identifying novel therapies for effective eradication of this disease.
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Affiliation(s)
| | - Oliver Prince
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO 63130
| | - Andrea Cooper
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 7RH, United Kingdom
| | - Shabaana A Khader
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO 63130
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Interleukin-35 (IL-35) inhibits proliferation and promotes apoptosis of fibroblast-like synoviocytes isolated from mice with collagen-induced arthritis. Mol Biol Rep 2016; 43:947-56. [PMID: 27379996 DOI: 10.1007/s11033-016-4034-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 06/29/2016] [Indexed: 01/13/2023]
Abstract
Rheumatoid arthritis (RA) is an inflammatory disorder of the joints that affects 0.5-1 % of adults. Excessive growth of the fibroblast-like synoviocytes (FLS) promotes hyperplasia of synovial tissues and causes its invasion into the bone and cartilage, which eventually causes deformity and dysfunction of affected joints. Interleukin 35 (IL-35) was shown to suppress the inflammatory responses to collagen-induced arthritis (CIA) via upregulation of T regulatory cells and suppression of T helper type 17 cells in a mouse model. To study the effects of IL-35 on the proliferation and apoptosis frequency of cultured FLS isolated from mice with CIA as well as to examine the effects of IL-35 on CIA in vivo. Thirty DBA/1 J mice, which are used as an animal model for RA, were divided randomly (ten mice per group) to a CIA group (collagen treatment), a CIA + IL-35 group (collagen and IL-35 treatments), and a control group (no treatment). Starting on the 24th day after collagen administration, IL-35 was injected intraperitoneally into mice of the CIA + IL-35 group once per day for 10 days. An arthritis index was calculated, and pathological analysis of synovial tissue was performed. FLS isolated from CIA mice were treated with various concentrations of IL-35 (12.5-100 ng/ml). The MTT assay was used to examine FLS proliferation, and apoptosis frequency of FLS was detected by flow cytometry. On day 24, the CIA mice began to exhibit arthritis symptoms, and the symptoms rapidly progressed with time. Treatment with IL-35 significantly alleviated arthritis symptoms and reduced the synovial tissue inflammation. In addition, IL-35 treatment inhibited proliferation and promoted apoptosis in cultured FLS from CIA mice in a dose-dependent manner. IL-35 could ameliorate the symptoms of arthritis in the CIA mouse model in vivo and inhibited FLS proliferation while promoting FLS apoptosis in vitro, thereby exhibited the potential in inhibiting the progression of RA.
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Angelica acutiloba Kitagawa Extract Attenuates DSS-Induced Murine Colitis. Mediators Inflamm 2016; 2016:9275083. [PMID: 27293323 PMCID: PMC4886075 DOI: 10.1155/2016/9275083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/27/2016] [Indexed: 12/13/2022] Open
Abstract
We examined the protective effects of Angelica acutiloba Kitagawa (AAK) extract on a murine model of acute experimental colitis. Colitis was induced by 4% dextran sulfate sodium (DSS) in the drinking water of male C57BL/6 mice, for 7 consecutive days. Oral administration of AAK extract (500 mg/kg/day) significantly alleviated DSS-induced symptoms such as anorexia, weight loss, events of diarrhea or bloody stools, and colon shortening. Histological damage was also ameliorated, as evidenced by the architectural preservation and suppression of inflammatory cell infiltration in colonic samples. Treatment improved the colonic mRNA expression of different inflammatory markers: cytokines, inducible enzymes, matrix metalloproteinases, and tight junction-related proteins. In the isolated serum, IgE levels were downregulated. Collectively, these findings indicate the therapeutic potentials of AAK as an effective complementary or alternative modality for the treatment of ulcerative colitis.
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Deschemin JC, Allouche S, Brouillard F, Vaulont S. Iron Homeostasis and Inflammatory Status in Mice Deficient for the Cystic Fibrosis Transmembrane Regulator. PLoS One 2015; 10:e0145685. [PMID: 26709821 PMCID: PMC4699203 DOI: 10.1371/journal.pone.0145685] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/07/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Cystic Fibrosis (CF) is a frequent and lethal autosomal recessive disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Patients with CF suffer from chronic infections and severe inflammation, which lead to progressive pulmonary and gut diseases. Recently, an expanding body of evidence has suggested that iron homeostasis was abnormal in CF with, in particular, systemic iron deficiency and iron sequestration in the epithelium airway. The molecular mechanisms responsible for iron dysregulation and the relationship with inflammation in CF are unknown. METHODS AND RESULTS We assessed the impact of CFTR deficiency on systemic and tissue iron homeostasis as well as inflammation in wildtype and CFTR knockout (KO) mice. First, in contrast to the systemic and intestinal inflammation we observed in the CFTR KO mice, we reported the absence of lung phenotype with regards to both inflammation and iron status. Second, we showed a significant decrease of plasma ferritin levels in the KO mice, as in CF patients, likely caused by a decrease in spleen ferritin levels. However, we measured unchanged plasma iron levels in the KO mice that may be explained by increased intestinal iron absorption. CONCLUSION These results indicate that in CF, the lung do not predominantly contributes to the systemic ferritin deficiency and we propose the spleen as the major organ responsible for hypoferritinemia in the KO mouse. These results should provide a better understanding of iron dysregulation in CF patients where treating or not iron deficiency remains a challenging question.
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Affiliation(s)
- Jean-Christophe Deschemin
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Laboratory of Excellence GR-Ex, Paris, France
| | - Sarah Allouche
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Laboratory of Excellence GR-Ex, Paris, France
| | - Franck Brouillard
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Gif-sur-Yvette, France
| | - Sophie Vaulont
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Laboratory of Excellence GR-Ex, Paris, France
- * E-mail:
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Kudo H, Wang Z, Jinnin M, Nakayama W, Inoue K, Honda N, Nakashima T, Kajihara I, Makino K, Makino T, Fukushima S, Ihn H. EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin. THE JOURNAL OF IMMUNOLOGY 2015; 195:3565-73. [DOI: 10.4049/jimmunol.1402362] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 08/05/2015] [Indexed: 01/30/2023]
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Zundler S, Neurath MF. Interleukin-12: Functional activities and implications for disease. Cytokine Growth Factor Rev 2015; 26:559-68. [PMID: 26182974 DOI: 10.1016/j.cytogfr.2015.07.003] [Citation(s) in RCA: 146] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 07/01/2015] [Indexed: 02/01/2023]
Abstract
Interleukin-12 (IL-12) was the first member of the IL-12 family of cytokines to be identified and has therefore become its eponym. It is a heterodimeric protein of two subunits (p35, p40) secreted by phagocytic cells in response to pathogens and mainly acts through STAT4 to induce IFN-γ production in T and NK cells. IFN-γ in turn mediates proinflammatory functions and activates T-bet. As IL-12 engages in TH1 development, it is believed to represent an important link between innate and adaptive immunity. Following its identification and the finding of its association to TH1 commitment, great hopes were placed in IL-12 to become a target for therapeutic applications in multiple settings of autoimmunity and cancer. Though, the discovery of the related members of the IL-12 family and several rather disappointing attempts to translate experimental results into clinical practice, have relativized these hopes. Nevertheless, IL-12 remains a cytokine of outstanding importance with lots of unresolved questions. In this review, we will first briefly depict the biochemistry of the cytokine, its receptor and the related signal transduction, before summarizing the regulation of IL-12 production and its biological functions. We will then describe the current knowledge about the implication of IL-12 in different murine disease models as well as in the corresponding human conditions and comment on possible consequences for future clinical applications.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Medical Clinic 1, Ulmenweg 18, 91054 Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Medical Clinic 1, Ulmenweg 18, 91054 Erlangen, Germany.
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Shi YY, Dai MJ, Wu GP, Zhou PP, Fang Y, Yan XB. Levels of interleukin-35 and its relationship with regulatory T-cells in chronic hepatitis B patients. Viral Immunol 2015; 28:93-100. [PMID: 25494369 PMCID: PMC4334469 DOI: 10.1089/vim.2014.0058] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Interleukin-35 is a novel inhibition cytokine secreted by CD4+CD25+ regulatory T-cells (Treg) in murine. However, it is disputed whether IL-35 could be secreted by Treg cells in humans. In this study, the levels of IL-35 were detected, and its relationship with regulatory T-cells in chronic hepatitis B (CHB) patients was investigated. It was shown that the levels of IL-35 in CHB patients were higher than those in normal controls, and the levels increased gradually, accompanied with the severe liver inflammation and necrosis and poor synthesis function. Treg cells may secrete IL-35, whose levels would become higher, accompanied by a longer activated time. Thus, IL-35 as a cytokine secreted by Treg cells may accelerate liver inflammation and necrosis, and inhibit the synthesis function.
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Affiliation(s)
- Yin-yue Shi
- Department of Infectious Diseases, First Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
- Department of Infectious Diseases, Xuzhou Children's Hospital, Xuzhou, China
| | - Ming-jia Dai
- Department of Infectious Diseases, First Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
| | - Gui-ping Wu
- Department of Infectious Diseases, First Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
| | - Pei-pei Zhou
- Department of Infectious Diseases, First Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
| | - Yuan Fang
- Department of Infectious Diseases, First Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
| | - Xue-bing Yan
- Department of Infectious Diseases, First Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
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Mitani A, Niedbala W, Fujimura T, Mogi M, Miyamae S, Higuchi N, Abe A, Hishikawa T, Mizutani M, Ishihara Y, Nakamura H, Kurita K, Ohno N, Tanaka Y, Hattori M, Noguchi T. Increased expression of interleukin (IL)-35 and IL-17, but not IL-27, in gingival tissues with chronic periodontitis. J Periodontol 2014; 86:301-9. [PMID: 25272982 DOI: 10.1902/jop.2014.140293] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Interleukin (IL)-35 plays an important role in immune regulation through the suppression of effector T-cell populations, including T-helper 17 (Th17) cells. Although Th17 cells and IL-17 are involved in the pathogenesis of periodontitis, the level of IL-35 in inflamed periodontal tissues is unclear. Here, IL-35, IL-17, and IL-27 production/expression in gingival crevicular fluid (GCF) and human gingival tissue were investigated. METHODS GCF samples were collected from buccal (mesial, center, and distal) sites of teeth from patients with chronic periodontitis (CP) and healthy controls and were analyzed by enzyme-linked immunosorbent assay for IL-35 (periodontitis, n = 36; healthy, n = 30) and IL-17 (periodontitis, n = 16; healthy, n = 13). Gingival tissue, including sulcus/pocket epithelium and underlying connective tissue, was collected from an additional 10 healthy participants and 10 patients with CP and were analyzed by quantitative polymerase chain reaction (qPCR) for Epstein Barr virus-induced gene 3 (EBI3), IL12A, and IL17A. IL27p28 was also tested by qPCR. RESULTS IL-35 and IL-17 were significantly higher in GCF from patients with periodontitis than healthy participants (P <0.01, P <0.05, respectively). In both healthy participants and those with periodontitis, positive correlations were found among IL-35 and probing depth and clinical attachment level (CAL) as well as between IL-17 and CAL. EBI3, IL12A (components of IL-35), and IL17A messenger RNA expression levels were significantly higher in inflamed gingival tissue than in healthy control tissues (P <0.05). IL27p28 was not detected in any sample, suggesting that IL-27 is not produced in large quantities in periodontal tissue. CONCLUSION IL-35 and IL-17, but not IL-27, may play important roles in the pathogenesis of periodontitis.
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Affiliation(s)
- Akio Mitani
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
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Kaser A. Not all monoclonals are created equal - lessons from failed drug trials in Crohn's disease. Best Pract Res Clin Gastroenterol 2014; 28:437-49. [PMID: 24913383 DOI: 10.1016/j.bpg.2014.04.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 04/03/2014] [Accepted: 04/13/2014] [Indexed: 01/31/2023]
Abstract
The recent success of the anti-integrin antibody Vedolizumab can barely conceal the fact that the biologics armamentarium in Crohn's disease has barely evolved beyond TNF blockers so far. This contrasts with other immune-related diseases considered mechanistically and genetically closely related, such as psoriasis and rheumatoid arthritis, where approved biologics target a variety of independent biological mechanisms. Several pharmacological assets that entered clinical development have proven ineffective, or less effective than originally anticipated. While blockade of IL-17A and its receptor via Secukinumab and Brodalumab, respectively, worsened Crohn's disease, the beneficial effect of IL-12/23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn's disease patients who have previously failed on TNF blockers. Clinical development of the IFNγ blocker Fontolizumab was stopped despite demonstrating some clinical benefit, while the T cell co-stimulation blocker Abatacept did not exhibit any hint towards efficacy in Crohn's disease. Here I review results from these individual development programmes, and also reflect on the lack of efficacy of the TNF blocker Etanercept. I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years. Finally, I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn's disease.
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Affiliation(s)
- Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, United Kingdom.
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19
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Lautenschläger C, Schmidt C, Lehr CM, Fischer D, Stallmach A. PEG-functionalized microparticles selectively target inflamed mucosa in inflammatory bowel disease. Eur J Pharm Biopharm 2013; 85:578-86. [DOI: 10.1016/j.ejpb.2013.09.016] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 09/17/2013] [Accepted: 09/20/2013] [Indexed: 12/20/2022]
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20
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Rafa H, Saoula H, Belkhelfa M, Medjeber O, Soufli I, Toumi R, de Launoit Y, Moralès O, Nakmouche M, Delhem N, Touil-Boukoffa C. IL-23/IL-17A axis correlates with the nitric oxide pathway in inflammatory bowel disease: immunomodulatory effect of retinoic acid. J Interferon Cytokine Res 2013; 33:355-68. [PMID: 23472658 DOI: 10.1089/jir.2012.0063] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn's disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.
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Affiliation(s)
- Hayet Rafa
- Team: Cytokines and NO Synthases, Laboratory of Cellular and Molecular Biology (LBCM), Faculty of Biological Science, USTHB, Algiers, Algeria
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Ancelet L, Rich FJ, Delahunt B, Kirman JR. Dissecting memory T cell responses to TB: concerns using adoptive transfer into immunodeficient mice. Tuberculosis (Edinb) 2012; 92:422-33. [PMID: 22738879 DOI: 10.1016/j.tube.2012.05.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2012] [Revised: 05/10/2012] [Accepted: 05/11/2012] [Indexed: 02/02/2023]
Abstract
Several studies have used adoptive transfer of purified T cell subsets into immunodeficient mice to determine the subset of T cells responsible for mediating protection against Mycobacterium tuberculosis. These studies suggested that CD62L(hi) memory CD4(+) T cells from BCG-vaccinated mice are key for protection against tuberculosis. Importantly, we observed that transfer of naïve CD4(+) T cells into Rag1-/- recipients protected against a mycobacterial challenge as well as transfer of BCG-experienced CD4(+) T cells. We found that transfer of total CD4(+) T cells from naïve mice or enriched CD62L(hi)CD4(+) T cells from BCG-vaccinated mice into Rag1-/- recipients induced severe colitis by 3 weeks post cell transfer, whereas transfer of CD62L(lo)CD4(+) T cells from BCG-vaccinated mice did not. Naïve and CD62L(hi)CD4(+) T cells proliferated extensively upon transfer and developed an activated effector phenotype in the lung, even in the absence of infectious challenge. The induction of colitis and systemic cytokine response induced by the transfer and subsequent activation of CD4(+) T cells from naïve mice or CD62L(hi)CD4(+) T cells from BCG-vaccinated mice, into immunodeficient recipients, may heighten their ability to protect against mycobacterial challenge. This raises doubts about the validity of this model to study CD4(+) T cell-mediated protection against tuberculosis.
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Affiliation(s)
- Lindsay Ancelet
- Infectious Diseases Group, Malaghan Institute of Medical Research, PO Box 7060, Newtown, Wellington 6242, New Zealand.
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Rutella S, Locatelli F. Intestinal dendritic cells in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2011; 17:3761-75. [PMID: 21987618 PMCID: PMC3181437 DOI: 10.3748/wjg.v17.i33.3761] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 01/18/2011] [Accepted: 01/25/2011] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract harbors a large number and diverse array of commensal bacteria and is an important entry site for pathogens. For these reasons, the intestinal immune system is uniquely dedicated to protect against infections, while avoiding the development of destructive inflammatory responses to the microbiota. Several models have been proposed to explain how the immune system discriminates between, and appropriately responds to, commensal and pathogenic microorganisms. Dendritic cells (DCs) and regulatory T cells (Treg) are instrumental in maintaining immune homeostasis and tolerance in the gut. DCs are virtually omnipresent and are remarkably plastic, having the ability to adapt to the influences of the microenvironment. Different DC populations with partially overlapping phenotypic and functional properties have been described in different anatomical locations. DCs in the draining mesenteric lymph nodes, in the intestinal lamina propria and in Peyer’s patches partake both in the control of intestinal inflammation and in the maintenance of gut tolerance. In this respect, gut-resident DCs and macrophages exert tolerogenic functions as they regularly encounter and sense commensal bacteria. In contrast, migrating DC subsets that are recruited to the gut as a result of pathogenic insults initiate immune responses. Importantly, tolerogenic DCs act by promoting the differentiation and expansion of Treg cells that efficiently modulate gut inflammation, as shown both in pre-clinical models of colitis and in patients with inflammatory bowel disease (IBD). This article reviews the phenotypic and functional features of gut DC subsets and discusses the current evidence underpinning the DC contribution to the pathogenesis of the major clinical subtypes of human IBD. It also addresses the potential clinical benefit derived from DC targeting either in vivo or in vitro.
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Immunoregulatory cytokines are associated with protection from immunopathology following Mycobacterium avium subspecies paratuberculosis infection in red deer. Infect Immun 2011; 79:2089-97. [PMID: 21321071 DOI: 10.1128/iai.00779-10] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Although the causative agent of Johne's disease, Mycobacterium avium subsp. paratuberculosis, is well known, the etiology of disease and the immune responses generated in response to infection are still poorly understood. Knowledge of definitive markers of protective immunity, infection, and the establishment of chronic granulomatous Johne's disease is necessary to advance vaccine and diagnostic development. We sought to profile the immune responses occurring within jejunal lymph nodes of experimentally challenged red deer (Cervus elaphus). Quantitative PCR was utilized to measure a range of cytokines, signaling molecules, and transcription factors involved in Th1, Th2, Treg, and Th17 immune responses. Significant differences in gene expression were observed between control, minimally diseased, and severely diseased animals, with severely diseased animals showing elevated proinflammatory transcripts and reduced anti-inflammatory transcripts. We identified a proinflammatory cytokine milieu of gamma interferon, interleukin-1α (IL-1α), and IL-17, which may contribute to the immunopathology observed during clinical Johne's disease and suggest that Th2 and Treg immune responses may play an important role in controlling the development of immunopathology in infected animals.
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Méndez-Samperio P. Role of interleukin-12 family cytokines in the cellular response to mycobacterial disease. Int J Infect Dis 2009; 14:e366-71. [PMID: 19762261 DOI: 10.1016/j.ijid.2009.06.022] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2009] [Revised: 06/12/2009] [Accepted: 06/16/2009] [Indexed: 02/06/2023] Open
Abstract
Interleukin (IL)-12 is a multifunctional cytokine acting as a key regulator of cell-mediated immune responses through the differentiation of naïve CD4+ T cells into type 1 helper T cells (Th1) producing interferon-gamma. As our knowledge of IL-12 family members is rapidly growing, it will be important to specify their involvement in the regulation of mycobacterial infection. This article is a review of the current knowledge regarding the functions of the IL-12 family cytokines in the immune host defense system against mycobacteria. Specifically, this review aims to describe recent scientific evidence concerning the protective role of some members of the IL-12 family cytokines for the control of mycobacterial infection, as well as to summarize knowledge of the potential use of the IL-12 family members as potent adjuvants in the prevention and treatment of mycobacterial infectious diseases. In addition, recent data supporting the importance of the IL-12 family members in mycobacterial diseases in relation to Th17 function are discussed. This examination will help to improve our understanding of the immune response to mycobacterial infection and also improve vaccine design and immunotherapeutic intervention against tuberculosis.
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Affiliation(s)
- Patricia Méndez-Samperio
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, México, DF 11340 Mexico.
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