|
1
|
Mititelu A, Grama A, Colceriu MC, Benţa G, Popoviciu MS, Pop TL. Role of Interleukin 6 in Acute Pancreatitis: A Possible Marker for Disease Prognosis. Int J Mol Sci 2024; 25:8283. [PMID: 39125854 PMCID: PMC11311934 DOI: 10.3390/ijms25158283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/24/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Acute pancreatitis (AP) is a significant cause of morbidity, even in children, and is frequently associated with systemic manifestations. There are many cytokines involved in the inflammatory response characteristic of this disease. Interleukin 6 (IL-6) is one of the most important cytokines involved in AP, beginning from cellular injury and continuing to the systemic inflammatory response and distant organ involvement. IL-6 is a multifunctional cytokine that regulates acute-phase response and inflammation. It is produced by various cells and exerts its biological role on many cells through its high-affinity complex receptor. IL-6 has been investigated as a predicting maker for severe forms of AP. Many studies have validated the use of IL-6 serum levels in the first 48 h as a reliable marker for severe evolution and multisystemic involvement. Still, it has not been used in daily practice until now. This review discusses the main binding mechanisms by which IL-6 triggers cellular response and the AP pathogenetic mechanisms in which IL-6 is involved. We then emphasize the promising role of IL-6 as a prognostic marker, which could be added as a routine marker at admission in children with AP.
Collapse
Affiliation(s)
- Alexandra Mititelu
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Marius-Cosmin Colceriu
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
| | - Gabriel Benţa
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
| | | | - Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| |
Collapse
|
|
2
|
Groza Y, Jemelkova J, Kafkova LR, Maly P, Raska M. IL-6 and its role in IgA nephropathy development. Cytokine Growth Factor Rev 2022; 66:1-14. [PMID: 35527168 DOI: 10.1016/j.cytogfr.2022.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 04/05/2022] [Indexed: 02/07/2023]
Abstract
IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes. Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria. This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.
Collapse
Affiliation(s)
- Yaroslava Groza
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Jana Jemelkova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic
| | - Leona Raskova Kafkova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic.
| | - Petr Maly
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic.
| |
Collapse
|
|
3
|
Tan AHJ, Vinanica N, Campana D. Chimeric antigen receptor-T cells with cytokine neutralizing capacity. Blood Adv 2020; 4:1419-1431. [PMID: 32271901 PMCID: PMC7160280 DOI: 10.1182/bloodadvances.2019001287] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 03/09/2020] [Indexed: 12/20/2022] Open
Abstract
Infusion of T lymphocytes expressing chimeric antigen receptors (CARs) can produce extraordinary antitumor activity in patients with leukemia, lymphoma, and myeloma. The signaling mechanisms activating T cells and provoking tumor cell killing also trigger cytokine secretion and macrophage activation, leading to cytokine release syndrome (CRS). CRS is a serious side effect of CAR-T cells, and proinflammatory interleukin-6 (IL-6) is central to its pathogenesis. To endow T cells with anti-CRS activity, we designed a nonsignaling membrane-bound IL-6 receptor (mbaIL6) constituted by a single chain variable fragment derived from an anti-IL-6 antibody linked to a transmembrane anchoring peptide. We found that mbaIL6 expressed on the surface of T cells could rapidly remove IL-6 from the culture supernatant. IL-6 removal was proportional to the number of mbaIL6+ cells, increased with T-cell proliferation, and neutralized IL-6 signaling and function. A construct encoding for mbaIL6 and an anti-CD19-41BB-CD3ζ CAR allowed simultaneous expression of both receptors. T cells with mbaIL6 and CAR neutralized macrophage-derived IL-6 while exerting powerful antitumor activity. Cytotoxicity and proliferation were identical to those of cells expressing CAR alone in vitro, and CAR-T cells were effective in xenograft models regardless of mbaIL6 expression. Levels of human IL-6 in mice, however, were greatly reduced if T cells expressed both receptors instead of CAR alone. Thus, CAR-T cells with on-board capacity to extinguish IL-6 represent a new approach to prevent CRS and suppress its severity without affecting the antitumor potential of CAR-T cells.
Collapse
Affiliation(s)
- Adrian H J Tan
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Natasha Vinanica
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Dario Campana
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| |
Collapse
|
|
4
|
Interleukin-6 signaling regulates hematopoietic stem cell emergence. Exp Mol Med 2019; 51:1-12. [PMID: 31649245 PMCID: PMC6813302 DOI: 10.1038/s12276-019-0320-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 04/19/2019] [Accepted: 05/30/2019] [Indexed: 12/20/2022] Open
Abstract
Hematopoietic stem cells (HSCs) produce all lineages of mature blood cells for the lifetime of an organism. In vertebrates, HSCs derive from the transition of the hemogenic endothelium (HE) in the floor of the embryonic dorsal aorta. Most recently, a series of proinflammatory factors, such as tumor necrosis factor-α, interferon-γ, and Toll-like receptor 4, have been confirmed to play a key role in HSC specification. However, the full complement of necessary signaling inputs remains unknown to date. Here, we show that interleukin-6R (IL6R) via IL6 is required and sufficient for HSC generation. We found that Notch activates IL6R by regulating its expression in the HE and in HSCs. The secretion of IL6 mainly originates from HSC-independent myeloid cells, but not from HSCs and their adjacent vascular endothelial cells. In addition, blocking IL6 signaling does not affect vascular development or the production of primitive erythrocytes. Taken together, our results uncover a previously obscure relationship between IL6 signaling and HSC production and provide new insights into HSC regeneration using proinflammatory factors in vitro. A molecule that triggers inflammation, interleukin-6 (IL6), is crucial for development of blood stem cells, known as hematopoetic stem cells (HSCs). HSCs can differentiate into any type of blood or immune cell, and have enormous therapeutic potential. Although some of the signaling molecules that trigger their development are known, HSCs have yet to be grown under laboratory conditions, so knowledge gaps remain. Based on clues that IL6 might be one of the missing signals, He Huang at the Zhejiang University School of Medicine, Hangzhou, China, and coworkers investigated how IL6 affects HSC development in zebrafish, a common model of development. Zebrafish embryos lacking IL6 were deficient in HSCs, but showed normal blood vessel growth. Treating with IL6 restored HSC production. These results represent another step toward being able to grow HSCs for transplantation and therapy.
Collapse
|
|
5
|
Wang X, Hao GL, Wang BY, Gao CC, Wang YX, Li LS, Xu JD. Function and dysfunction of plasma cells in intestine. Cell Biosci 2019; 9:26. [PMID: 30911371 PMCID: PMC6417281 DOI: 10.1186/s13578-019-0288-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/01/2019] [Indexed: 12/23/2022] Open
Abstract
As the main player in humoral immunity, antibodies play indispensable roles in the body's immune system. Plasma cells (PCs), as antibody factories, are important contributors to humoral immunity. PCs, recognized by their unique marker CD138, are always discovered in the medullary cords of spleen and lymph nodes and in bone marrow and mucosal lymphoid tissue. This article will review the origin and differentiation of PCs, characteristics of short- and long-lived PCs, and the secretion of antibodies, such as IgA, IgM, and IgG. PCs play a crucial role in the maintenance of intestinal homeostasis using immunomodulation though complex mechanisms. Clearly, PCs play functional roles in maintaining intestinal health, but more details are needed to fully understand all the other effects of intestinal PCs.
Collapse
Affiliation(s)
- Xue Wang
- School of Basic Medical Sciences, Xuanwu Hospital, Beijing Capital Medical University, Beijing, 100069 China
| | - Gui-liang Hao
- School of Basic Medical Sciences, Xuanwu Hospital, Beijing Capital Medical University, Beijing, 100069 China
| | - Bo-ya Wang
- Peking University Health Science Center, Beijing, 100081 China
| | - Chen-chen Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, No. 10, Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Yue-xiu Wang
- Department of Teaching Office, International School, Capital Medical University, Beijing, 100069 China
| | - Li-sheng Li
- Function Platform Center, School of Basic Medical Science, Capital Medical University, Beijing, 100069 China
| | - Jing-dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, No. 10, Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| |
Collapse
|
|
6
|
Sen M, Johnston PA, Pollock NI, DeGrave K, Joyce SC, Freilino ML, Hua Y, Camarco DP, Close DA, Huryn DM, Wipf P, Grandis JR. Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines. J Chem Biol 2017; 10:129-141. [PMID: 28684999 DOI: 10.1007/s12154-017-0169-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 04/06/2017] [Indexed: 12/13/2022] Open
Abstract
Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6Rα-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead activities: a triazolothiadiazine (864669), amino alcohol (856350), and an oxazole-piperazine (4248543). We demonstrated that all three blocked IL-6-induced upregulation of the cyclin D1 and Bcl-XL STAT3 target genes. None of the compounds exhibited direct binding interactions with STAT3 in surface plasmon resonance (SPR) binding assays; neither did they inhibit the recruitment and binding of a phospho-tyrosine-gp130 peptide to STAT3 in a fluorescence polarization assay. Furthermore, they exhibited little or no inhibition in a panel of 83 cancer-associated in vitro kinase profiling assays, including lack of inhibition of IL-6-induced Janus kinase (JAK 1, 2, and 3) activation. Further, 864669 and 4248543 selectively inhibited IL-6-induced STAT3 activation but not that induced by oncostatin M (OSM). The compounds 864669 and 4248543 abrogated IL-6-induced phosphorylation of the gp130 signaling subunit (phospho-gp130Y905) of the IL-6-receptor complex in HNSCC cell lines which generate docking sites for the SH2 domains of STAT3. Our data indicate that 864669 and 4248543 block IL-6-induced STAT activation by interfering with the recruitment, assembly, or activation of the hexamer-activated IL-6/IL-6Rα/gp130 signaling complex that occurs after IL-6 binding to IL-6Rα subunits.
Collapse
Affiliation(s)
- Malabika Sen
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Paul A Johnston
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Netanya I Pollock
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Kara DeGrave
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Sonali C Joyce
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Maria L Freilino
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Yun Hua
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Daniel P Camarco
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - David A Close
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Donna M Huryn
- University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260 USA
| | - Peter Wipf
- University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260 USA
| | - Jennifer R Grandis
- Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94118 USA.,Clinical and Translational Science Institute, University of California, San Francisco, Box 0558, 550 16th Street, San Francisco, CA 94143 USA
| |
Collapse
|
|
7
|
Abstract
Castleman's disease is a rare condition characterized by benign hyperplastic lymph nodes. Based on the morphological features, it has been divided into hyaline-vascular, plasma cell and intermediate types. The latter two types are frequently associated with a wide variety of clinical pictures such as fever, anemia with hypotransferrinemia, hyperimmunoglobulinemia and an increase in the concentration of C-reactive protein (CRP). Although immunological disturbances have been suggested to play important roles in the pathophysiology of Castleman's disease, the precise mechanisms for the generation of its clinical pictures are still unsettled. In this respect, we have reported a pediatric case with spontaneous production of high levels of B cell differentiation factor (BCDF) activity by the hyperplastic lymph node, and we demonstrated here the strong expression of interleukin 6 (IL-6) gene in the lymph node cells. On the other hand, recent studies have revealed that IL-6 is a multifunctional cytokine; IL-6 not only induces the immunoglobulin production but also induces the acute phase reaction, and functions as an endogeneous pyrogen. In the acute phase reaction, IL-6 may induce an increase in CRP concentration and hypotransferrinemia. These studies indicate that the overproduction of IL-6 by the hyperplastic lymph node may be closely related to the pathophysiology of Castleman's disease. Therefore, it is considered that this disease is a "disorder of IL-6 production".
Collapse
Affiliation(s)
- A Yabuhara
- a Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - A Komiyama
- a Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| |
Collapse
|
|
8
|
Abstract
Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.
Collapse
Affiliation(s)
- Christopher A Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Simon A Jones
- Cardiff Institute of Infection and Immunity, The School of Medicine, Cardiff University, Heath Campus, Cardiff, UK
| |
Collapse
|
|
9
|
IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015; 16:448-57. [DOI: 10.1038/ni.3153] [Citation(s) in RCA: 1392] [Impact Index Per Article: 139.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 03/19/2015] [Indexed: 02/07/2023]
|
|
10
|
Le TTT, Karmouty-Quintana H, Melicoff E, Le TTT, Weng T, Chen NY, Pedroza M, Zhou Y, Davies J, Philip K, Molina J, Luo F, George AT, Garcia-Morales LJ, Bunge RR, Bruckner BA, Loebe M, Seethamraju H, Agarwal SK, Blackburn MR. Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 193:3755-68. [PMID: 25172494 PMCID: PMC4169999 DOI: 10.4049/jimmunol.1302470] [Citation(s) in RCA: 231] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 07/31/2014] [Indexed: 12/20/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
Collapse
Affiliation(s)
- Thanh-Thuy T Le
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030
| | - Harry Karmouty-Quintana
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | | | - Thanh-Truc T Le
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | - Tingting Weng
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | - Ning-Yuan Chen
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | - Mesias Pedroza
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030; Biology of Inflammation Center, Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
| | - Yang Zhou
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | - Jonathan Davies
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
| | - Kemly Philip
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | - Jose Molina
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | - Fayong Luo
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030
| | - Anuh T George
- Biology of Inflammation Center, Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
| | - Luis J Garcia-Morales
- Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and
| | - Raquel R Bunge
- Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and
| | - Brian A Bruckner
- Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and Methodist J.C. Walter Jr. Transplant Center, The Methodist Hospital, Houston, TX 77030
| | - Matthias Loebe
- Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and Methodist J.C. Walter Jr. Transplant Center, The Methodist Hospital, Houston, TX 77030
| | - Harish Seethamraju
- Methodist J.C. Walter Jr. Transplant Center, The Methodist Hospital, Houston, TX 77030
| | - Sandeep K Agarwal
- Biology of Inflammation Center, Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
| | - Michael R Blackburn
- Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030;
| |
Collapse
|
|
11
|
Cansby E, Nerstedt A, Amrutkar M, Durán EN, Smith U, Mahlapuu M. Partial hepatic resistance to IL-6-induced inflammation develops in type 2 diabetic mice, while the anti-inflammatory effect of AMPK is maintained. Mol Cell Endocrinol 2014; 393:143-51. [PMID: 24976178 DOI: 10.1016/j.mce.2014.06.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 06/19/2014] [Accepted: 06/19/2014] [Indexed: 11/19/2022]
Abstract
Interleukin-6 (IL-6) induces hepatic inflammation and insulin resistance, and therapeutic strategies to counteract the IL-6 action in liver are of high interest. In this study, we demonstrate that acute treatment with AMP-activated protein kinase (AMPK) agonists AICAR and metformin efficiently repressed IL-6-induced hepatic proinflammatory gene expression and activation of STAT3 in a mouse model of diet-induced type 2 diabetes, bringing it back to basal nonstimulated level. Surprisingly, the inflammatory response in liver induced by IL-6 administration in vivo was markedly blunted in the mice fed a high-fat diet, compared to lean chow-fed controls, while this difference was not replicated in vitro in primary hepatocytes derived from these two groups of mice. In summary, our work reveals that partial hepatic IL-6 resistance develops in the mouse model of type 2 diabetes, while the anti-inflammatory action of AMPK is maintained. Systemic factors, rather than differences in intracellular IL-6 receptor signaling, are likely mediating the relative impairment in IL-6 effect.
Collapse
Affiliation(s)
- Emmelie Cansby
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden
| | - Annika Nerstedt
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden
| | - Manoj Amrutkar
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden
| | - Esther Nuñez Durán
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden
| | - Ulf Smith
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden
| | - Margit Mahlapuu
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
| |
Collapse
|
|
12
|
Interleukin-6 signal transduction and its role in hepatic lipid metabolic disorders. Cytokine 2014; 66:133-42. [PMID: 24491813 DOI: 10.1016/j.cyto.2013.12.017] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Revised: 12/14/2013] [Accepted: 12/30/2013] [Indexed: 01/12/2023]
Abstract
Hepatic lipid dysregulation can lead to spectrum of metabolic disease conditions including metabolic syndrome (MS), fatty liver and diabetes. Liver lipids are regulated by a complex set of extra-hepatic and intra-hepatic factors including cellular cross-talk with variety of cells, inducing various cytokines. Interleukin 6(IL-6) is a pleiotropic cytokine that exerts both pro-inflammatory and anti-inflammatory effects on hepatic system through either JNK/STAT or ERK/MAPK signaling. Although, IL-6 has shown to protect the liver from fat storage in both rodent and human models and various IL-6(-/-) studies have supported this notion yet a question remains over its deleterious pro-inflammatory effects on hepatocytes. IL-6 ability to produce reactive oxygen species (ROS) and subsequently disturb the hepatic lipid balance has created a conundrum. Furthermore, IL-6 has shown to behave differently under different disease states within hepatocytes and hence, modulating the hepatic lipids accordingly. This review deals with the role of IL-6 on hepatic lipid metabolism and analyzes various data presented on this topic.
Collapse
|
|
13
|
Aydın AF, Develi-İş S, Doğru-Abbasoğlu S, Vural P, Ozderya A, Karadağ B, Uysal M. Polymorphisms of endothelin 1 (G5665T and T-1370G) and endothelin receptor type A (C+70G and G-231A) in Graves' disease. Int Immunopharmacol 2013; 18:198-202. [PMID: 24291390 DOI: 10.1016/j.intimp.2013.11.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 11/07/2013] [Accepted: 11/19/2013] [Indexed: 10/25/2022]
Abstract
PURPOSE Endothelin 1 (EDN1) is a strong angiogenic and mitogenic factor, playing a key role in hypervascularization, thyroid follicle cell hyperplasia, and lymphocyte infiltration in the thyroid gland of patients with Graves' disease (GD). EDN1 induces angiogenesis and mitogenesis via endothelin receptor type A (EDNRA). This study examined the possible association of EDN1 (G5665T and T-1370G) and EDNRA (C+70G and G-231A) single nucleotide polymorphisms (SNPs) with the occurrence of GD, and evaluates the relationship between genotypes and clinical/laboratory manifestations of GD. MATERIALS AND METHODS We analyzed genotype and allele distributions of EDN1 and EDNRA polymorphisms in 165 patients with GD and 181 healthy controls by real-time PCR combined with melting curve analysis. RESULTS No significant associations between GD and variant alleles of the studied polymorphisms were observed. However, the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) levels in EDN1 G5665T GG genotype were higher than those in T allele carriers (GT+TT) (p=0.001 and p=0.026, respectively). In addition, anti-TPO levels in EDN1 T-1370G wild-type homozygous patients were found to be higher than in mutant gene carrying patients (GT+GG) (p=0.006). The presence of EDNRA+70G allele was associated with 3.37-fold increased risk for development of ophthalmopathy in GD patients (p=0.009). CONCLUSION Although there were no associations between EDN1 (G5665T and T-1370G) and EDNRA (C+70G and G-231A) SNPs and susceptibility to GD, EDN1 G5665T and T-1370G polymorphisms were related to alterations of autoantibody production and EDNRA C+70G polymorphism is related with increased risk for ophthalmopathy in GD patients.
Collapse
Affiliation(s)
- A Fatih Aydın
- Istanbul University, Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul, Turkey
| | - Seval Develi-İş
- Istanbul University, Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul, Turkey
| | - Semra Doğru-Abbasoğlu
- Istanbul University, Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul, Turkey
| | - Pervin Vural
- Istanbul University, Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul, Turkey.
| | - Ayşenur Ozderya
- Şişli Etfal Education and Research Hospital, II. Internal Medicine Clinic, Department of Endocrinology, Şişli, 34387 Istanbul, Turkey
| | - Berrin Karadağ
- Şişli Etfal Education and Research Hospital, II. Internal Medicine Clinic, Department of Endocrinology, Şişli, 34387 Istanbul, Turkey
| | - Müjdat Uysal
- Istanbul University, Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul, Turkey
| |
Collapse
|
|
14
|
Abstract
The formation of the cellular constituents of the blood is regulated by a series of endogenous polypeptides with largely paracrine function. A number of these hematopoietic growth factors (HGF's), which include colony stimulating factors, interleukins, and erythropoietin, have been purified to homogeneity and cloned, which in turn has led to extensive investigations of their biochemical properties and biological effects and functions. The HGF's act on target cells by binding to receptors. The kinetics and, to an even larger extent, dynamics of the factor/receptor associations display several intriguing characteristics, most of which are still poorly understood. Herein, the biochemical characteristics of HGF's receptors as well as the binding properties, post-receptor binding events and receptor modulation resulting from the association of HGF's and their target cells are reviewed.
Collapse
|
|
15
|
The combination of ınterleukin-10 −1082 and tumor necrosis factor α −308 or ınterleukin-6 −174 genes polymorphisms suggests an association with susceptibility to Hashimoto's thyroiditis. Int Immunopharmacol 2012; 12:543-6. [DOI: 10.1016/j.intimp.2012.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Revised: 01/25/2012] [Accepted: 02/07/2012] [Indexed: 12/19/2022]
|
|
16
|
Meyer C, Eydeler K, Magbanua E, Zivkovic T, Piganeau N, Lorenzen I, Grötzinger J, Mayer G, Rose-John S, Hahn U. Interleukin-6 receptor specific RNA aptamers for cargo delivery into target cells. RNA Biol 2012; 9:67-80. [PMID: 22258147 PMCID: PMC3342945 DOI: 10.4161/rna.9.1.18062] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Aptamers represent an emerging strategy to deliver cargo molecules, including dyes, drugs, proteins or even genes, into specific target cells. Upon binding to specific cell surface receptors aptamers can be internalized, for example by macropinocytosis or receptor mediated endocytosis. Here we report the in vitro selection and characterization of RNA aptamers with high affinity (Kd = 20 nM) and specificity for the human IL-6 receptor (IL-6R). Importantly, these aptamers trigger uptake without compromising the interaction of IL-6R with its natural ligands the cytokine IL-6 and glycoprotein 130 (gp130). We further optimized the aptamers to obtain a shortened, only 19-nt RNA oligonucleotide retaining all necessary characteristics for high affinity and selective recognition of IL-6R on cell surfaces. Upon incubation with IL-6R presenting cells this aptamer was rapidly internalized. Importantly, we could use our aptamer, to deliver bulky cargos, exemplified by fluorescently labeled streptavidin, into IL-6R presenting cells, thereby setting the stage for an aptamer-mediated escort of drug molecules to diseased cell populations or tissues.
Collapse
Affiliation(s)
- Cindy Meyer
- Institute for Biochemistry and Molecular Biology; Chemistry Department; MIN-Faculty; Hamburg University; Hamburg, Germany
| | - Katja Eydeler
- Institute for Biochemistry and Molecular Biology; Chemistry Department; MIN-Faculty; Hamburg University; Hamburg, Germany
| | - Eileen Magbanua
- Institute for Biochemistry and Molecular Biology; Chemistry Department; MIN-Faculty; Hamburg University; Hamburg, Germany
| | - Tijana Zivkovic
- Institute for Biochemistry and Molecular Biology; Chemistry Department; MIN-Faculty; Hamburg University; Hamburg, Germany
| | - Nicolas Piganeau
- Institute for Biochemistry and Molecular Biology; Chemistry Department; MIN-Faculty; Hamburg University; Hamburg, Germany
| | - Inken Lorenzen
- Institute of Biochemistry; Medical Faculty; Christian-Albrechts-University; Kiel, Germany
| | - Joachim Grötzinger
- Institute of Biochemistry; Medical Faculty; Christian-Albrechts-University; Kiel, Germany
| | - Günter Mayer
- Life and Medical Sciences Institute; University of Bonn; Bonn, Germany
| | - Stefan Rose-John
- Institute of Biochemistry; Medical Faculty; Christian-Albrechts-University; Kiel, Germany
| | - Ulrich Hahn
- Institute for Biochemistry and Molecular Biology; Chemistry Department; MIN-Faculty; Hamburg University; Hamburg, Germany
| |
Collapse
|
|
17
|
IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 2011; 122:143-59. [PMID: 22029668 DOI: 10.1042/cs20110340] [Citation(s) in RCA: 612] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6-sIL-6R complex can then form a complex with gp130. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)/ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK/STAT (signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize the IL-6/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and pathological roles of IL-6.
Collapse
|
|
18
|
Takai H, Kato A, Nakamura T, Tachibana T, Sakurai T, Nanami M, Suzuki M. The importance of characterization of FITC-labeled antibodies used in tissue cross-reactivity studies. Acta Histochem 2011; 113:472-6. [PMID: 20546862 DOI: 10.1016/j.acthis.2010.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2010] [Revised: 04/14/2010] [Accepted: 04/15/2010] [Indexed: 11/29/2022]
Abstract
Fluorescein isothiocyanate (FITC)-labeled antibodies are widely used as primary antibodies in the tissue cross-reactivity (TCR) studies for the development of therapeutic antibodies. However, the effects of FITC-labeling on the characteristics of an antibody are poorly understood. The present study was performed to examine the effect of FITC-labeling on the binding affinity and immunohistochemical staining profile of an antibody, using several antibodies with different FITC-labeling indices. The results showed that the FITC-labeling index in antibody was negatively correlated with the binding affinity for its target antigen. Immunohistochemically, an antibody with a higher labeling index had a tendency to be more sensitive, but was also more likely to yield non-specific staining. Based on these findings, we recommend that a FITC-labeled antibody used as a primary antibody in a TCR study should be carefully selected from several differently labeled antibodies to minimize the decrease in the binding affinity and achieve the appropriate sensitivity and interpretation of the immunohistochemistry.
Collapse
Affiliation(s)
- Hirotake Takai
- Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Lissilaa R, Buatois V, Magistrelli G, Williams AS, Jones GW, Herren S, Shang L, Malinge P, Guilhot F, Chatel L, Hatterer E, Jones SA, Kosco-Vilbois MH, Ferlin WG. Although IL-6 trans-signaling is sufficient to drive local immune responses, classical IL-6 signaling is obligate for the induction of T cell-mediated autoimmunity. THE JOURNAL OF IMMUNOLOGY 2010; 185:5512-21. [PMID: 20870936 DOI: 10.4049/jimmunol.1002015] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IL-6-mediated T cell-driven immune responses are associated with signaling occurring through the membrane-bound cognate receptor α-chain (mIL-6Rα). Once formed, IL-6-mIL-6Rα complexes induce the homodimerization and subsequent phosphorylation of the ubiquitously expressed signal-transducing protein, gp130. This signaling event is defined as classical IL-6 signaling. However, many inflammatory processes assigned to IL-6 may be mediated via binding a naturally occurring soluble IL-6Rα, which forms an agonistic complex (IL-6/soluble IL-6Rα) capable of evoking responses on a wide range of cell types that lack mIL-6Rα (IL-6 trans-signaling). To dissect the differential contribution of the two IL-6 signaling pathways in cell-mediated inflammatory processes, we pharmaceutically targeted each using two murine models of human arthritis. Whereas intra-articular neutralization of trans-signaling attenuated local inflammatory responses, the classical pathway was found to be obligate and sufficient to induce pathogenic T cells and humoral responses, leading to systemic disease. Our data illustrate that mechanisms occurring in the secondary lymphoid organs underlying arthropathies are mediated via the classical pathway of IL-6 signaling, whereas trans-signaling contributes only at the local site, that is, in the affected tissues.
Collapse
|
|
20
|
Brown RD, Gorenc B, Gibson J, Warburton P, Joshua D. Interleukin 4 and 6 Receptor Expression on B Cell Lines and the Lymphocytes of Patients with B Cell Malignancies. Leuk Lymphoma 2009. [DOI: 10.3109/10428199209053570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- R. D. Brown
- Haematology Department, Royal Prince Alfred Hospital, Sydney, Australia
| | - B. Gorenc
- Haematology Department, Royal Prince Alfred Hospital, Sydney, Australia
| | - J. Gibson
- Haematology Department, Royal Prince Alfred Hospital, Sydney, Australia
| | - P. Warburton
- Haematology Department, Royal Prince Alfred Hospital, Sydney, Australia
| | - D. Joshua
- Haematology Department, Royal Prince Alfred Hospital, Sydney, Australia
| |
Collapse
|
|
21
|
Okamoto Y, Nakajo I, Seta K, Gotoh Y, Nagai T, Fujita N, Fukui T, Masuzawa T. Urinary evaluation of the balance between soluble interferon-gamma receptor (IFN-gammaR1) and interleukin-4 receptor (IL-4Ralpha). Int Immunopharmacol 2008; 8:1859-62. [PMID: 18809513 DOI: 10.1016/j.intimp.2008.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2008] [Revised: 08/28/2008] [Accepted: 09/01/2008] [Indexed: 11/29/2022]
Abstract
To elucidate the usefulness of the simultaneous analysis of multiple kinds of soluble cytokine receptors in urine specimens, we determined the levels of both the soluble interferon-gamma receptor alpha chain (sIFN-gammaR1, Th1-type cytokine receptor) and the soluble interleukin 4-receptor alpha chain (sIL-4Ralpha, Th2-type cytokine receptor) in the urine of healthy subjects as reference values and preliminarily applied this method to evaluate patients with diarrhea positive (D+) hemolytic uremic syndrome (HUS) as the diagnostic parameters. The urinary sIFN-gammaR levels of children were significantly lower than those of adults (p < 0.01, n = 107). On the other hand, there was no significant difference between the urine sIL-4R levels of adults and children. Statistical correlation between sIFN-gammaR and sIL-4R values was not observed (p = 0.705). On the day of onset of HUS, the urine sIFN-gammaR levels of the patients (n = 6) with HUS were higher than those of the healthy control group (n = 67) (p < 0.01); however, there was no significant difference in the sIL-4R levels between both groups. The urine evaluation of the balance between the soluble cytokine receptors might be informative for the immune states of HUS patients.
Collapse
Affiliation(s)
- Yoshihiro Okamoto
- Laboratory of Immunology and Microbiology, Faculty of Pharmacy, Chiba Institute of Science, 3 Shiomi-cho, Choshi, Chiba 288-0025, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Gangavarapu KJ, Olbertz JL, Bhushan A, Lai JCK, Daniels CK. Apoptotic resistance exhibited by dexamethasone-resistant murine 7TD1 cells is controlled independently of interleukin-6 triggered signaling. Apoptosis 2008; 13:1394-400. [PMID: 18819004 DOI: 10.1007/s10495-008-0265-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Interleukin-6 (IL6)-mediated signaling is known to play a role in pathogenesis and resistance in several cancers like multiple myeloma (MM). In this report we used the IL6-dependent 7TD1 murine B-cell hybridoma as an in vitro model to study the interactions between IL6-signaling pathways and the development of dexamethasone resistance. Though in initial stages, 7TD1 cells grew IL6-dependent and were sensitive to dexamethasone-induced apoptosis, chronic exposure to dexamethasone led to a dexamethasone-resistant phenotype (7TD1-Dxm) that grew independent of exogenous IL6. While IL6-mediated JAK/STAT3 and PI3K/AKT signaling was important for proliferation of both cell lines, as shown in proliferation assays using the respective pathway inhibitors, AG490 and LY294002, the resistant cells were insensitive to induction of apoptosis using the same. STAT3 was constitutively phosphorylated in resistant cells and inhibition of its dimerization induced apoptosis but did not alter their insensitivity to dexamethasone. Our results suggest a role of entities downstream of IL6-mediated JAK/STAT3 signaling in development of dexamethasone resistance by 7TD1-Dxm cells.
Collapse
Affiliation(s)
- Kalyan J Gangavarapu
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Campus Box 8334, Pocatello, ID 83209, USA
| | | | | | | | | |
Collapse
|
|
23
|
Kato A, Watanabe T, Yamazaki M, Deki T, Suzuki M. IL-6R distribution in normal human and cynomolgus monkey tissues. Regul Toxicol Pharmacol 2008; 53:46-51. [PMID: 19010373 DOI: 10.1016/j.yrtph.2008.10.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2008] [Revised: 10/17/2008] [Accepted: 10/21/2008] [Indexed: 11/16/2022]
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine and a contributing factor in many diseases such as rheumatoid arthritis, Castleman's disease, Crohn's disease, and multiple myeloma. Since the blockade of the signaling pathway of the IL-6/interleukin-6 receptor (IL-6R)/gp130 complex is considered to have therapeutic value in such diseases, we developed an IL-6R humanized antibody (tocilizumab). In the current report, distribution of IL-6R in both normal human and cynomolgus monkey tissues was assessed as fundamental data to support preclinical and clinical studies of tocilizumab. Human and cynomolgus monkey tissue panels were stained with commercially available anti-human IL-6R and a species- and isotype-matched negative antibody, as well as assay control slides. The detection system applied used an Envision immunoperoxidase staining procedure with DAB reaction. Positive reactions were observed in the tissue elements of lymphatic, hematopoietic, digestive, reproductive, exocrine, endocrine, neural, muscular, epidermal, respiratory, and urinary systems of the human and cynomolgus monkey tissue panels. The current report is inclusive of a wide variety of tissues and shows the distribution of IL-6R to be similar for both human and monkey tissues. We consider this information fundamental for the support and interpretation of preclinical and clinical studies of anti-IL-6R antibody therapy.
Collapse
Affiliation(s)
- Atsuhiko Kato
- Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
| | | | | | | | | |
Collapse
|
|
24
|
Hashizume M, Mihara M. Influence of humanized anti-IL-6R antibody, tocilizumab on the activity of soluble gp130, natural inhibitor of IL-6 signaling. Rheumatol Int 2008; 29:397-401. [DOI: 10.1007/s00296-008-0703-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2008] [Accepted: 09/07/2008] [Indexed: 11/30/2022]
|
|
25
|
Hirano T, Taga T, Yamasaki K, Matsuda T, Yasukawa K, Hirata Y, Yawata H, Tanabe O, Akira S, Kishimoto T. Molecular cloning of the cDNAs for interleukin-6/B cell stimulatory factor 2 and its receptor. Ann N Y Acad Sci 2008; 557:167-78, discussion 178-80. [PMID: 2786692 DOI: 10.1111/j.1749-6632.1989.tb24010.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- T Hirano
- Division of Cellular Immunology, Osaka University, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Snyers L, Fontaine V, Content J. Modulation of interleukin-6 receptors in human cells. Ann N Y Acad Sci 2008; 557:388-93; discussion 394-5. [PMID: 2786701 DOI: 10.1111/j.1749-6632.1989.tb24031.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- L Snyers
- Département de Virologie, Institut Pasteur du Brabant, Brussels, Belgium
| | | | | |
Collapse
|
|
27
|
|
|
28
|
Tosato G, Pike SE. A monocyte-derived B cell growth factor is IFN-beta 2/BSF-2/IL-6. Ann N Y Acad Sci 2008; 557:181-90, discussion 190-1. [PMID: 2544130 DOI: 10.1111/j.1749-6632.1989.tb24011.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- G Tosato
- Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892
| | | |
Collapse
|
|
29
|
Kishimoto T, Hibi M, Murakami M, Narazaki M, Saito M, Taga T. The molecular biology of interleukin 6 and its receptor. CIBA FOUNDATION SYMPOSIUM 2007; 167:5-16; discussion 16-23. [PMID: 1425018 DOI: 10.1002/9780470514269.ch2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Functional pleiotropy and redundancy are characteristic features of cytokines. Interleukin 6 (IL-6) is a typical example: IL-6 induces cellular differentiation or expression of tissue-specific genes; it is involved in processes such as antibody production in B cells, acute-phase protein synthesis in hepatocytes, megakaryocyte maturation, cytotoxic T cell differentiation, and neural differentiation of PC12 (pheochromocytoma) cells. It promotes growth of myeloma/plasmacytoma cells, T cells, keratinocytes and renal mesangial cells, and it inhibits growth of myeloid leukaemic cell lines and certain carcinoma cell lines. The IL-6 receptor consists of two polypeptide chains, a ligand-binding chain (IL-6R) and a non-ligand-binding, signal-transducing chain (gp130). Interaction of IL-6 with IL-6R triggers the association of gp130 and IL-6R, and the signal can be transduced through gp130. Association of gp130 with IL-6R is involved in the formation of high affinity binding sites. This two-chain model has been shown to be applicable to receptor systems for several other cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-5 and nerve growth factor (NGF). The pleiotropy and redundancy of cytokines may be explained on the basis of this unique receptor system.
Collapse
Affiliation(s)
- T Kishimoto
- Department of Medicine III, Osaka University Medical School, Japan
| | | | | | | | | | | |
Collapse
|
|
30
|
Chen R, Chang C, Chen W, Tsai C, Tsai F. Proinflammatory cytokine gene polymorphisms among Hashimoto's thyroiditis patients. J Clin Lab Anal 2007; 20:260-5. [PMID: 17115419 PMCID: PMC6807634 DOI: 10.1002/jcla.20152] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Proinflammatory cytokines are involved in the pathogenesis of Hashimoto's thyroiditis (HT). To test whether certain specific proinflammatory cytokine gene polymorphisms could be genetic markers for an individual's susceptibility to HT, we investigated single-site polymorphisms of certain proinflammatory cytokine genes of interest for 107 HT sufferers and 163 controls, subsequent to preparing the necessary experimental genomic DNA from peripheral blood, using a polymerase chain reaction (PCR)-based restriction analysis. The polymorphisms we detected were as follows: 1) C/T and E1/E2 polymorphisms for the interleukin (IL)-1beta gene at promoter (-511) and exon 5, respectively; 2) a variable number of tandem repeats (VNTRs) for the IL-1 receptor antagonist (IL-1Ra) gene at intron 2; 3) a C/G polymorphism for the IL-6 gene at promoter (-572); and 4) an A/G polymorphism for the tumor necrosis factor (TNF)-alpha gene at promoter (-308). The data demonstrated an increased ratio of CG genotype and decreased ratios of CC and GG genotypes (chi-squared test; P = 0.025) for the IL-6 gene promoter for HT patients when compared with normal controls. The odds ratio (OR) for the CG genotype, as compared to the GG genotype, for HT patients was shown to be 4.065 (95% confidence interval (CI): 1.268-13.032). Comparison of the genotype analysis for the remaining gene polymorphisms and the allelic analysis for all of the screened gene polymorphisms, however, all revealed no statistically significant difference between the two study groups as regards frequency of genotype. In conclusion, we suggest that an IL-6 gene promoter (-572) C/G polymorphism could represent a potential "candidate" genetic marker to predict an individual's susceptibility to HT.
Collapse
Affiliation(s)
- Rong‐Hsing Chen
- Department of Medicine, China Medical University Hospital, China Medical University, China
| | - Chwen‐Tzuei Chang
- Department of Medicine, China Medical University Hospital, China Medical University, China
| | - Wei‐Chi Chen
- Department of Urology, China Medical University Hospital, China Medical University, China
- Department of Medical Genetics, China Medical University Hospital, China Medical University, China
| | - Chang‐Hai Tsai
- Department of Pediatrics, China Medical University Hospital, China Medical University, China
- Department of Bioinformatics, Asia University; Taichung, Taiwan
| | - Fuu‐Jen Tsai
- Department of Medical Genetics, China Medical University Hospital, China Medical University, China
- Department of Pediatrics, China Medical University Hospital, China Medical University, China
| |
Collapse
|
|
31
|
Horiuchi S, Yamamoto N, Dewan MZ, Takahashi Y, Yamashita A, Yoshida T, Nowell MA, Richards PJ, Jones SA, Yamamoto N. Human T-cell leukemia virus type-I Tax induces expression of interleukin-6 receptor (IL-6R): Shedding of soluble IL-6R and activation of STAT3 signaling. Int J Cancer 2006; 119:823-30. [PMID: 16557588 DOI: 10.1002/ijc.21918] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Human T-cell leukemia virus type-I (HTLV-I) encodes for the viral protein Tax, which is known to significantly disrupt transcriptional control of cytokines, cytokine receptors and other immuno-modulatory proteins in T cells. Specific dysregulation of these factors can alter the course and pathogenesis of infection. Soluble interleukin-6 receptor (sIL-6R) was shown to circulate at elevated levels in HTLV-I-infected patients, and high expressions of IL-6R and sIL-6R by HTLV-I-infected T cells were clinically and experimentally associated with Tax activity. To examine roles of Tax in expression of the IL-6R gene, the JPX-9 cell line was used, which is derived from Jurkat cell line expressing Tax cDNA. Over-expression of Tax enhanced IL-6R expression but not in Tax mutant JPX-9/M cell line. The clinical relevance of these observations was further demonstrated by ELISA using sera obtained from HTLV-I-infected patients. Our results revealed that sIL-6R levels were apparently elevated in HAM/TSP patients who were expressing Tax in their cells, while ATL patients' cells barely expressed Tax. HTLV-I-infected T-cell lines stimulated by IL-6/sIL-6R showed gp130-mediated STAT3 activity. IL-6/sIL-6R enhanced proliferation of HTLV-I-infected T cells in association with activation of STAT3. Consequently, Tax-mediated regulations of IL-6R and sIL-6R observed in HTLV-I-associated disorders may contribute to proliferation of HTLV-I-infected T cells through activation of inducible STAT3, and ultimately affect malignant growth and transformation of T cells by HTLV-I.
Collapse
Affiliation(s)
- Sankichi Horiuchi
- Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Sugimoto K, Nishimoto N, Kishimoto T, Yoshizaki K, Nishimura T. Imaging of lesions in a murine rheumatoid arthritis model with a humanized anti-interleukin-6 receptor antibody. Ann Nucl Med 2005; 19:261-6. [PMID: 16097634 DOI: 10.1007/bf02984617] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Rheumatoid arthritis (RA) has been attributed to the abnormal production of cytokine interleukin-6 (IL-6), which has a variety of physiological activities. In vivo IL-6-receptor imaging provides useful suggestions regarding the mechanism of anti-IL-6-receptor antibody action and indicates a basic therapeutic strategy for treating RA. Therefore, this study was designed to establish a method for radiolabeling anti-IL-6-receptor antibodies and to investigate the feasibility of using radiolabeled anti-IL-6-receptor antibodies in the scintigraphic imaging of lesions in an animal RA model. Anti-IL-6-receptor antibodies were conjugated with a bifunctional chelating agent, hydrazinonicotinamide (HYNIC), and radiolabeled with technetium-99m (99mTc) using the ligand exchange reaction of 99mTc-tricine complex. The binding affinity was estimated using the U266 cell line. Whole body scintigraphy, biodistribution and autoradiography were undertaken in mice containing synovial cells that had been transplanted from an RA patient. Our findings showed that the antibodies accumulated in the implanted tissue. When radiolabeled anti-IL-6-receptor antibodies are used in scintigraphic imaging, the distribution of the IL-6-receptors is associated with the inflammatory cell infiltration that is seen in the early stage of RA. Accordingly, imaging with humanized anti-IL-6-receptor antibodies appears to be useful for detecting early pathophysiological conditions and assessing the efficacy of antibody treatment as well as the prognosis of patients with RA.
Collapse
Affiliation(s)
- Kanji Sugimoto
- Division of Tracer Kinetics, Osaka University Graduate School of Medicine
| | | | | | | | | |
Collapse
|
|
33
|
|
|
34
|
Hirata T, Shimazaki C, Sumikuma T, Ashihara E, Goto H, Inaba T, Koishihara Y, Nakagawa M. Humanized anti-interleukin-6 receptor monoclonal antibody induced apoptosis of fresh and cloned human myeloma cells in vitro. Leuk Res 2003; 27:343-9. [PMID: 12531226 DOI: 10.1016/s0145-2126(02)00179-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We investigated the effect of anti-IL-6 receptor monoclonal antibody (hPM1) on the in vitro proliferation of cloned and freshly isolated myeloma cells from 20 patients with advanced stage multiple myeloma (MM). Humanized PM1 significantly inhibited the growth of a myeloma cell line in a dose-dependent manner and inhibited more than 30% of the proliferation of fresh myeloma cells in 10 of the 19 cases. Flow cytometric analysis using annexin V and 7AAD showed that hPM1 induced apoptosis of myeloma cells. These observations suggest the possibility of using hPM1 for treating some patients with MM whose growth depends on IL-6.
Collapse
Affiliation(s)
- Toshiyuki Hirata
- Second Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyoku, Kyoto 602-8566, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Luo Y, Chen X, O'Donnell MA. Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect. Cytokine 2003; 21:17-26. [PMID: 12668155 DOI: 10.1016/s1043-4666(02)00490-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Induction of a T-helper-type 1 (Th1) immune response is indispensable for successful treatment of superficial bladder cancer with BCG. In this study possible involvement of various cytokines in BCG action as well as their potential roles in enhancing and mimicking BCG effect were explored. In immunocompetent cell cultures, IFN-gamma, a major Th1 cytokine, appears to be a late responsive cytokine to BCG stimulation. Its induction requires involvement of various endogenously produced Th1 and Th2 cytokines. Functional abolishment of any one of these cytokines (IL-2, IL-6, IL-12, IL-18, GMCSF, TNF-alpha, or IFN-alpha, except IL-10) by neutralizing antibodies leads to reduced IFN-gamma production (19-82% inhibition in mouse and 44-77% inhibition in human systems, respectively). In mice cytokines IL-2, IL-12, IL-18, and GMCSF are observed to synergize with BCG for IFN-gamma production, whereas in human cytokines IL-2, IL-12, TNF-alpha, and IFN-alpha exhibit similar synergistic effects. Rational combinations of these Th1-stimulating cytokines (IL-12 plus IL-18 in mice and IL-2 plus IL-12 in humans, respectively) dramatically up-regulate IFN-gamma production that is incomparably superior to BCG for induction of this cytokine. These results suggest that combined Th1-stimulating cytokines and combinations of BCG plus selected Th1-stimulating cytokines are rational candidates for further study in the treatment of bladder cancer patients.
Collapse
Affiliation(s)
- Yi Luo
- Department of Urology, University of Iowa Hospitals and Clinics, 200 Hawkins Avenue, Iowa City, IA 52242, USA
| | | | | |
Collapse
|
|
36
|
Canellada A, Blois S, Gentile T, Margni Idehu RA. In vitro modulation of protective antibody responses by estrogen, progesterone and interleukin-6. Am J Reprod Immunol 2002; 48:334-43. [PMID: 12516657 DOI: 10.1034/j.1600-0897.2002.01141.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PROBLEM We have previously demonstrated that the addition of placental interleukin-6 (IL-6) to murine hybridomas increased asymmetric antibody synthesis. Here we analyze whether progesterone (Pg) and estrogen (E2) affect asymmetric antibody synthesis by modulating IL-6 production in hybridoma cells. METHOD OF STUDY Hybridoma 112D5 B cells were cultured with E2, Pg or recombinant IL-6. Cell proliferation was assessed by 3H-thymidine incorporation, and asymmetric antibodies were measured in culture supernatants by Con A fixation and enzyme-linked immunusorbant assay (ELISA). E2 and Pg-receptors (ER and PR) were evaluated in whole cell extracts by Western blot. IL-6 was measured in culture supernatants by ELISA. RESULTS 112D5 expressed both PR and ER, which were differentially regulated. At 48 hr, Pg and E2 slightly decreased cell proliferation whereas IL-6 did not. As well as IL-6, 10(-10) M Pg but not E2 induced asymmetric antibody production. Interestingly, Pg at 10(-6) M decreased asymmetric antibody synthesis by hybridoma cells. Finally, mainly Pg but also E2 increased IL-6 synthesis, although IL-6 levels did not correlate with asymmetric antibodies synthesized in the presence of E2 or Pg. CONCLUSIONS In cells expressing both ER and PR, we could demonstrate that steroids participate in humoral immune responses by modulating asymmetric antibody synthesis. IL-6 proved to be only partially involved. Other possible mechanisms involved in the effect of Pg on blocking antibody responses and their contribution to a successful pregnancy are discussed in the paper.
Collapse
Affiliation(s)
- Andrea Canellada
- Instituto de Estudios de la Inmunidad Humoral-Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad de Buenos Aires, Buenos Aires, Argentina.
| | | | | | | |
Collapse
|
|
37
|
Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002; 13:357-68. [PMID: 12220549 DOI: 10.1016/s1359-6101(02)00027-8] [Citation(s) in RCA: 596] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Interleukin 6 (IL-6), which was originally identified as a B-cell differentiation factor, is now known to be a multifunctional cytokine that regulates the immune response, hematopoiesis, the acute phase response, and inflammation. Deregulation of IL-6 production is implicated in the pathology of several disease processes. The expression of constitutively high levels of IL-6 in transgenic mice results in fatal plasmacytosis, which has been implicated in human multiple myeloma. Increased IL-6 levels are also observed in several diseases, including rheumatoid arthritis (RA), systemic-onset juvenile chronic arthritis (JCA), osteoporosis, and psoriasis. IL-6 is critically involved in experimentally induced autoimmune disease, such as antigen-induced arthritis (AIA), and experimental allergic encephalomyelitis. All these clinical data and animal models suggest that IL-6 plays critical roles in the pathogenesis of autoimmune diseases. Here we review the evidence for the involvement of IL-6 in the pathophysiology of autoimmune diseases and chronic inflammatory proliferative diseases (CIPD) and discuss the possible molecular mechanisms of its involvement.
Collapse
Affiliation(s)
- Katsuhiko Ishihara
- Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, 2-2 Yamada-oka Suita, Osaka 565-0871, Japan
| | | |
Collapse
|
|
38
|
Sasaki A, Ishiuchi S, Kanda T, Hasegawa M, Nakazato Y. Analysis of interleukin-6 gene expression in primary human gliomas, glioblastoma xenografts, and glioblastoma cell lines. Brain Tumor Pathol 2002; 18:13-21. [PMID: 11517969 DOI: 10.1007/bf02478920] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Our previous study showed that high-grade astrocytomas often expressed high interleukin (IL)-1beta production. Coexpression of IL-1beta and IL-6 has been found in a number of glioma samples and glioma cell lines. To characterize the expression of IL-6 in the human glioma microenvironment, we investigated surgically excised human gliomas, human glioblastoma xenografts, and human glioblastoma cell lines using the reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA). In the 29 primary gliomas, transcripts of IL-6 were less frequently detectable (55.6%) than those of IL-1beta (72.4%) or those of IL-10, IL-8, or IL-1alpha (>80% each). As for IL-6 gene expression, little or no transcription was observed in low-grade astrocytomas, oligodendroglial tumors, and 1 ependymoma. Strong IL-6 gene expression was found in only 5 of 9 glioblastomas. Immunohistochemically, IL-6 antigen was localized in the tumor cells and macrophages in 4 of 7 glioblastomas. In 3 glioblastomas transplanted into nude mice, both IL-1beta and IL-6 were detected only in 1, but othercytokines (IL-8, IL-10, and IL-1alpha) were detected in all 3 xenografts by RT-PCR. Two cell lines both showed IL-6 expression at the mRNA level, and in a cell line with a high level of IL-6 and IL-1beta transcripts, significant production of IL-6 was observed by IHC and ELISA. We concluded that IL-6 produced in tumor tissue may be involved in tumor progression in some glioblastomas, but not in low-grade astrocytomas and oligodendroglial tumors, and that IL-6 gene expression is closely correlated with IL-1beta expression in biopsy tissue, xenografts, and cultures of human gliomas.
Collapse
Affiliation(s)
- A Sasaki
- Department of Pathology, Gunma University School of Medicine, Maebashi, Japan.
| | | | | | | | | |
Collapse
|
|
39
|
Peppard JV, Loo P, Sills MA, Wennogle L, Wright A, Pomponi S, Cueto M. The discovery and characterization of an interleukin 6 cytokine family antagonist protein from a marine sponge, Callyspongia sp. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2002; 484:77-87. [PMID: 11419009 DOI: 10.1007/978-1-4615-1291-2_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2023]
|
|
40
|
Werner AM, Katner HP, Vogel R, Southerland SS, Ashley AV, Floyd JC, Brown C, Ashley DW. Delayed Vaccination Does Not Improve Antibody Responses in Splenectomized Rats Experiencing Hypovolemic Shock. Am Surg 2001. [DOI: 10.1177/000313480106700904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Delayed vaccination after splenectomy has been shown to increase the antibody response in normotensive rats. The purpose of this experiment was to study the effect of timing of vaccination on antibody responses in rats undergoing splenectomy and experiencing hypovolemic shock. Sixty male Sprague-Dawley rats weighing 250 to 400 g underwent either a sham abdominal surgery or splenectomy after a 30-minute period of controlled hypovolemic shock. All rats then received pneumococcal vaccinations one day, 7 days, or 28 days postoperatively. Antibody levels were determined by enzyme-linked immunosorbent assay 3 weeks after vaccination. Results were compared by analysis of variance. Animals vaccinated one day postoperatively had similar or higher antibody responses than did rats receiving delayed vaccinations after 7 or 28 days. These results were similar for immunoglobulins G and M and more importantly were consistent for animals undergoing splenectomy and sham operations. Delayed vaccinations failed to improve antibody responses when hypovolemic shock preceded splenectomy. We propose that this is the result of complex cytokine responses to hypovolemic shock. These responses have been studied extensively in the setting of septic shock but not in the setting of hypovolemic or hemorrhagic shock.
Collapse
Affiliation(s)
- Andrew M. Werner
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| | - Harold P. Katner
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| | - Robert Vogel
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| | - Sheila S. Southerland
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| | - Angela V. Ashley
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| | - John C.P. Floyd
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| | - Christopher Brown
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| | - Dennis W. Ashley
- Departments of Surgery and Internal Medicine, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia
| |
Collapse
|
|
41
|
Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 2000; 51:245-70. [PMID: 10774463 DOI: 10.1146/annurev.med.51.1.245] [Citation(s) in RCA: 849] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer's disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.
Collapse
Affiliation(s)
- W B Ershler
- Institute for the Advanced Studies in Aging and Geriatric Medicine, Washington, DC 20006, USA.
| | | |
Collapse
|
|
42
|
Igaz P, Horváth A, Horváth B, Szalai C, Pállinger E, Rajnavölgyi E, Tóth S, Rose-John S, Falus A. Soluble interleukin-6 receptor (sIL-6R) makes IL-6R negative T cell line respond to IL-6; it inhibits TNF production. Immunol Lett 2000; 71:143-8. [PMID: 10722865 DOI: 10.1016/s0165-2478(00)00157-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The receptor for interleukin-6 (IL-6) consists of two subunits: a ligand specific IL-6Ralpha and gp130 that is responsible for signal-transduction. A soluble form of the ligand specific chain was described that when complexed to IL-6 is capable of binding to the membrane-bound gp130 subunit and thus can elicit signal-transduction. This soluble receptor can act on cells that express only the gp130 but not the ligand-specific subunit of the IL-6R. This phenomenon, called trans-signaling, introduced a novel aspect of cytokine action. In this study we examined the response of Jurkat cells, that are known not to express IL-6Ralpha, to IL-6, the soluble IL-6 receptor (sIL-6R) and a covalent complex of IL-6 and sIL-6R termed Hyper-IL-6. We studied the expression of tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma). The complex of IL-6+sIL-6R and Hyper-IL-6 inhibited significantly the production of TNF in a gp130-dependent manner, whereas no differences in IFN-gamma expression were found. IL-6 and sIL-6R alone were not effective. Because we did not detect major differences in the TNF mRNA levels upon treatments, we conclude that the inhibition of TNF production should occur at the post-transcriptional level. These results provide another example of trans-signaling and underline the physiological importance of sIL-6R, and in the case of Hyper-IL-6 its possible therapeutic application can also be considered.
Collapse
Affiliation(s)
- P Igaz
- Department of Genetics, Cell- and Immunobiology, Semmelweis University Medical School, P.O. Box 370, Nagyvárad tér 4, 1445, Budapest, Hungary
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Abstract
The purpose of this study was to evaluate the presence of interleukin-6 (IL-6) in basal tears of contact lens wearers (n = 18) and nonlens wearers (n = 25). Samples (5 microl) were collected with a microcapillary pipette and evaluated using PAGE electrophoresis and immunoblot analysis. Contact lens-wearing patients had a mean IL-6 level of 43.8 +/- 5.3 pg/5 microl compared with nondetectable IL-6 levels throughout the noncontact lens-wearing population. IL-6 in several patients removed from contact lens wear for 6 days became nondetectable. When these patients were returned to wearing lenses, IL-6 levels increased to their original levels within 24 h. The data presented indicate that an ocular medical device may stimulate IL-6 production.
Collapse
Affiliation(s)
- C L Schultz
- Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
| | | |
Collapse
|
|
44
|
Tosato G, Teruya-Feldstein J, Setsuda J, Pike SE, Jones KD, Jaffe ES. Post-transplant lymphoproliferative disease (PTLD): lymphokine production and PTLD. SPRINGER SEMINARS IN IMMUNOPATHOLOGY 2000; 20:405-23. [PMID: 9870254 DOI: 10.1007/bf00838052] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- G Tosato
- Division of Hematologic Products, Food and Drug Administration, Bethesda, MD 20892, USA
| | | | | | | | | | | |
Collapse
|
|
45
|
Nishimoto N, Ito A, Ono M, Tagoh H, Matsumoto T, Tomita T, Ochi T, Yoshizaki K. IL-6 inhibits the proliferation of fibroblastic synovial cells from rheumatoid arthritis patients in the presence of soluble IL-6 receptor. Int Immunol 2000; 12:187-93. [PMID: 10653854 DOI: 10.1093/intimm/12.2.187] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
IL-6 and tumor necrosis factor (TNF)-alpha have been proven to play an important role in the development of rheumatoid arthritis (RA). It is well known that TNF-alpha induces IL-6 production from synovial cells as well as their proliferation. The effect of IL-6 on synovial cells, however, is not clear. An in vitrostudy was performed to determine the effect of IL-6 on the proliferation of synovial cells. Fibroblastic synovial cells isolated from the synovial tissues of eight RA patients were employed after the third to sixth passages. IL-6 in the presence of soluble IL-6 receptor (sIL-6R) inhibited the proliferation of synovial cells in a dose-dependent manner in seven cases without increasing the number of necrotic or apoptotic cells, while TNF-alpha increased synovial cell proliferation in all cases. The inhibitory effect of IL-6 was observed only in the presence of sIL-6R although small amounts of IL-6R were detected in these cells by RT-PCR analysis. However, anti-IL-6R or anti-gp130 mAb treatment increased spontaneous growth of synovial cells in all eight cases, suggesting that endogenous IL-6 and a small amount of IL-6R expressed in synovial cells suppressed their growth without exogenous IL-6 or sIL-6R. In addition, the IL-6-sIL-6R complex reduced the TNF-alpha-induced proliferation of synovial cells while TNF-alpha induced their IL-6 production. These data suggest that IL-6 may act as a negative feedback factor for TNF-alpha-induced synovial cell growth.
Collapse
Affiliation(s)
- N Nishimoto
- Department of Medical Science I, School of Health and Sport Sciences, Osaka University, 2-1 Yamadaoka, Suita-city, Osaka 565-0871, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Azuma H, Moriyama T, Ikeda H, Oshima M, Okuno A, Sekiguchi S. Analysis of soluble interleukin 6 receptor in cerebrospinal fluid in inflammatory and non-inflammatory conditions. Cytokine 2000; 12:160-4. [PMID: 10671302 DOI: 10.1006/cyto.1999.0534] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The objective of this study was to investigate the pathophysiological roles of soluble interleukin 6 receptor (sIL-6R) in cerebrospinal fluid (CSF). CSF was obtained from patients suspected with meningitis. Eight patients without any meningeal signs or symptoms were enrolled as controls. An additional 34 CSF samples were collected to measure both biologically active and immunoreactive sIL-6R. All CSF samples were proven to be aseptic. IL-6 and sIL-6R were measured using specific ELISAs. Patients were divided into three groups on the basis of cell number in CSF; inflammatory group (cell number >5 microl, mean 241+/-363.1, n=61); non-inflammatory group (cell number < or =5 microl, mean=2.1+/-1.7, n=12) and controls (cell number < or =5 microl, mean=0.3+1.7, n=8). Among these three groups, the differences in protein (F (2,78)=8.274, P<0.0001) and IL-6 concentration (F (2,78)=6.475, P<0.001) were statistically significant but those of sIL-6R concentration were not. There were only weak correlations between log (sIL-6R) versus log (cell number) (r=0.23, P=0.0375), log (protein) (r=0.239, P=0.0358) and log (IL-6) (r=0.27, P=0.0167). Amounts of immunoreactive and biologically active sIL-6R were closely correlated (r=0.62, n=34, P<0.005). It was concluded that sIL-6R is present constitutively in CSF and its level may not increase significantly in inflammatory conditions; infiltrating cells in CSF are not the main source of sIL-6R; and sIL-6R in CSF can bind IL-6.
Collapse
Affiliation(s)
- H Azuma
- Hokkaido Red Cross Blood Center Yamanote, 2-2 Nishi-ku, Sapporo, 063-0002, Japan.
| | | | | | | | | | | |
Collapse
|
|
47
|
Agematsu K, Hokibara S, Nagumo H, Shinozaki K, Yamada S, Komiyama A. Plasma cell generation from B-lymphocytes via CD27/CD70 interaction. Leuk Lymphoma 1999; 35:219-25. [PMID: 10706444 DOI: 10.3109/10428199909145724] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
To produce antibodies, the differentiation of B cells into antibody-secreting cells, plasma cells, is required. We describe that ligation of CD27, which belongs to the tumor necrosis factor receptor (TNFR) family and is a memory marker of B cells, yields crucial signals that positively control the entry of B cells into the pathway to plasma cells. The triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). The differentiation into plasma cells by a combination of IL-10 and CD70-transfectants occurred in CD27+ B cells, but not in CD27- B cells. Moreover, the addition of IL-2 to the IL-10 and CD70-transfectants greatly induced the differentiation into plasma cells. In the presence of only IL-2, IL-4 or IL-6, CD70-transfectants did not promote the differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B cell pool from peripheral blood B cells primarily activated by IL-2, IL-10 and anti-CD40 mAb. These data demonstrate that CD27 ligand (CD70) is a key molecule to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.
Collapse
Affiliation(s)
- K Agematsu
- From the Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
| | | | | | | | | | | |
Collapse
|
|
48
|
Interleukin-6 Regulation of Matrix Metalloproteinase (MMP-2 and MMP-9) and Tissue Inhibitor of Metalloproteinase (TIMP-1) Expression in Malignant Non-Hodgkin’s Lymphomas. Blood 1999. [DOI: 10.1182/blood.v94.6.2080.418k30_2080_2089] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We showed previously that human malignant non-Hodgkin’s lymphomas (NHL) degrade extracellular matrix (ECM) components through the action of metalloproteinases and that elevated expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) correlated with a poor clinical outcome in patients with NHL. In the present study we sought to investigate whether there is any correlation between the expression of gelatinases (MMP-2 and MMP-9), TIMP-1, and the expression of cytokines and growth factors such as interleukin-1β (IL-1β), IL-6, IL-10, tumor necrosis factor (TNF-), transforming growth factor β (TGFβ), and basic fibroblast growth factor (bFGF) in human NHL. In lymphoma tissues obtained from 32 patients, elevated expression of IL-6 correlated significantly with elevated messenger RNA (mRNA) levels of MMP-9, MMP-2, and TIMP-1. Moreover, in human lymphoid cell lines of B- and T-cell origin (Raji, Jurkat, and NC-37), IL-6 stimulated production of MMP-9 and MMP-2 but not TIMP-1. In the Matrigel invasion assay IL-6 significantly upregulated transmigration of Raji and Jurkat cells, which in turn was inhibited by recombinant human TIMP-1 and anti-MMP-9 and MMP-2 antibodies. We postulate that IL-6 may play a role in the clinical aggressiveness of human NHL by stimulating MMP production.
Collapse
|
|
49
|
Interleukin-6 Regulation of Matrix Metalloproteinase (MMP-2 and MMP-9) and Tissue Inhibitor of Metalloproteinase (TIMP-1) Expression in Malignant Non-Hodgkin’s Lymphomas. Blood 1999. [DOI: 10.1182/blood.v94.6.2080] [Citation(s) in RCA: 148] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractWe showed previously that human malignant non-Hodgkin’s lymphomas (NHL) degrade extracellular matrix (ECM) components through the action of metalloproteinases and that elevated expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) correlated with a poor clinical outcome in patients with NHL. In the present study we sought to investigate whether there is any correlation between the expression of gelatinases (MMP-2 and MMP-9), TIMP-1, and the expression of cytokines and growth factors such as interleukin-1β (IL-1β), IL-6, IL-10, tumor necrosis factor (TNF-), transforming growth factor β (TGFβ), and basic fibroblast growth factor (bFGF) in human NHL. In lymphoma tissues obtained from 32 patients, elevated expression of IL-6 correlated significantly with elevated messenger RNA (mRNA) levels of MMP-9, MMP-2, and TIMP-1. Moreover, in human lymphoid cell lines of B- and T-cell origin (Raji, Jurkat, and NC-37), IL-6 stimulated production of MMP-9 and MMP-2 but not TIMP-1. In the Matrigel invasion assay IL-6 significantly upregulated transmigration of Raji and Jurkat cells, which in turn was inhibited by recombinant human TIMP-1 and anti-MMP-9 and MMP-2 antibodies. We postulate that IL-6 may play a role in the clinical aggressiveness of human NHL by stimulating MMP production.
Collapse
|
|
50
|
März P, Heese K, Dimitriades-Schmutz B, Rose-John S, Otten U. Role of interleukin-6 and soluble IL-6 receptor in region-specific induction of astrocytic differentiation and neurotrophin expression. Glia 1999; 26:191-200. [PMID: 10340760 DOI: 10.1002/(sici)1098-1136(199905)26:3<191::aid-glia1>3.0.co;2-#] [Citation(s) in RCA: 133] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Increasing evidence supports an essential role for interleukin-6 (IL-6) in the development, differentiation, as well as de- and re-generation of neurons in the central nervous system (CNS). Both IL-6 and its specific receptor (IL-6R) are expressed on neurons and glial cells including astrocytes. In this study, we have analyzed the responses of primary rat astrocytes of various brain regions to IL-6 with respect to morphological changes and neurotrophin expression. Since IL-6 alone failed to initiate effects on astrocytes, we have examined whether the soluble IL-6R (sIL-6R) can modulate the responsiveness of to IL-6 in these cells. For this purpose, we used a highly active fusion protein of IL-6 and sIL-6R, which is designated Hyper-IL-6 (H-IL-6). We show that treatment of cultured astrocytes with Hyper-IL-6 promotes region-specific morphological changes of GFAP-positive astrocytes from typical stellate- to fibrous-like cells. In addition, we find that Hyper-IL-6 induces expression of neurotrophins (NTs) of the nerve growth factor (NGF)-family in a dose-dependent manner. Interestingly, astrocytes of various brain regions show differing patterns of cytokine-induced NT expression: NGF is maximally induced in cortex and hippocampus, NT-3 in hippocampus, and NT-4/5 in cortex and cerebellum. In summary, our results indicate that IL-6 in conjunction with sIL-6R regulates specific neurotrophin expression in astrocytes in a brain region dependent manner. Thus, the IL-6 system provides a local supply of neurotrophins that participate in diverse CNS functions such as protection of neurons from insults, neuronal survival, and neuro-immune responses.
Collapse
Affiliation(s)
- P März
- I. Med. Clinic, Section Pathophysiology, University of Mainz, Germany
| | | | | | | | | |
Collapse
|