Interleukin‐6 modulates production of T lymphocyte–derived cytokines in antigen‐induced arthritis and drives inflammation‐induced osteoclastogenesis

Wiley - Tập 54 Số 1 - Trang 158-168 - 2006
Peter K. K. Wong1, J Quinn2, Natalie A. Sims3, Annemarie van Nieuwenhuijze4, Ian K. Campbell4, Ian P. Wicks4
1Division of Autoimmunity and Transplantation, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
2St Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
3St Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria, Australia
4The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Tóm tắt

AbstractObjectiveTo determine the cellular mediators of antigen‐induced arthritis (AIA) and the relative contribution of members of the interleukin‐6 (IL‐6) family and tumor necrosis factor (TNF) in AIA.MethodsAIA was induced in mice deficient in T and B lymphocytes, IL‐6 (IL‐6−/−), TNF (TNF−/−), IL‐11 receptor, and oncostatin M receptor, by immunization with methylated bovine serum albumin (mBSA) followed 7 days later by intraarticular injection of mBSA. Arthritis severity was assessed histologically, and T lymphocyte responses were assessed in vitro. Anti‐TNF neutralizing antibody was administered to wild‐type mice during AIA. Bone marrow osteoclasts were generated in vitro via culture with RANKL and macrophage colony‐stimulating factor.ResultsAIA was dependent on CD4+ T lymphocytes, but not CD8+ T lymphocytes or B cells. IL‐6−/− mice had reduced AIA severity and fewer osteoclasts at sites of bone erosion. This protective effect was not seen with a deficiency of other IL‐6 family members and was similar to that in TNF−/− mice or wild‐type mice receiving TNF blockade treatment. IL‐6−/− CD4+ T lymphocytes from draining lymph nodes had reduced antigen‐induced proliferation and produced less IL‐17 and less RANKL, relative to osteoprotegerin, than cells from wild‐type mice. Bone marrow from IL‐6−/− mice generated fewer osteoclasts in vitro than bone marrow from either wild‐type or TNF−/− mice.ConclusionAIA is driven by CD4+ T lymphocytes. IL‐6 is an important mediator of bone destruction in AIA because it regulates T lymphocyte production of key osteoclastogenic cytokines and inflammation‐induced bone marrow osteoclast differentiation. These findings have implications for reducing bone and joint damage in rheumatoid arthritis.

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Tài liệu tham khảo

10.1038/nri802

10.1002/art.10168

10.1056/NEJM199707173370301

10.1002/1529-0131(200005)43:5<1001::AID-ANR7>3.0.CO;2-P

10.1146/annurev.immunol.23.021704.115806

Wendling D, 1993, Treatment of severe rheumatoid arthritis by anti‐interleukin 6 monoclonal antibody, J Rheumatol, 20, 259

10.1002/art.20303

10.1002/jbmr.5650110113

10.1002/art.1780400614

10.1172/JCI113921

10.1038/nrm763

10.1002/art.1780351012

10.1002/1529-0131(200002)43:2<250::AID-ANR3>3.0.CO;2-P

10.1038/46303

10.1002/1529-0131(200105)44:5<1003::AID-ANR179>3.0.CO;2-#

10.1016/S0092-8674(00)80209-3

Gravallese EM, 1998, Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis, Am J Pathol, 152, 943

10.4049/jimmunol.138.3.775

10.1359/jbmr.2000.15.8.1459

10.4049/jimmunol.169.6.3353

10.1172/JCI5703

10.1016/S8756-3282(01)00682-2

10.4049/jimmunol.170.5.2655

10.1002/art.1780200314

Brackertz D, 1977, Studies on antigen‐induced arthritis in mice. III. Cell and serum transfer experiments, J Immunol, 118, 1645, 10.4049/jimmunol.118.5.1645

10.3109/08820139609059316

10.1136/ard.2003.013060

10.1111/j.1365-2249.2003.02381.x

10.1006/cyto.1999.0502

10.1073/pnas.95.14.8222

10.4049/jimmunol.172.12.7408

10.4049/jimmunol.173.6.3844

10.1016/S0002-9440(10)64846-8

Kobayashi H, 2002, Antigen induced arthritis (AIA) can be transferred by bone marrow transplantation: evidence that interleukin 6 is essential for induction of AIA, J Rheumatol, 29, 1176

10.1038/368339a0

10.1172/JCI12724

10.1016/0092-8674(92)90030-G

10.1034/j.1399-3089.2000.00566.x

Serreze DV, 1994, Major histocompatibility complex class I‐deficient NOD‐β2m null mice are diabetes and insulitis resistant, Diabetes, 43, 505, 10.2337/diab.43.3.505

10.1038/350423a0

10.1182/blood.V90.6.2148

10.1182/blood-2003-02-0367

10.1002/1529-0131(200102)44:2<442::AID-ANR63>3.0.CO;2-M

10.1002/art.20382

10.1073/pnas.0404328101

10.4049/jimmunol.166.9.5327

10.1016/S8756-3282(01)00654-8

10.1002/jcb.10614

10.1172/JCI10483

10.1126/science.289.5484.1504

10.1038/35046102

10.1002/j.1460-2075.1994.tb06368.x

10.1002/art.10943

10.1016/j.cyto.2004.09.011

10.1002/1529-0131(200111)44:11<2697::AID-ART450>3.0.CO;2-#

10.1084/jem.183.6.2593

10.4049/jimmunol.160.7.3513

10.1002/1529-0131(200109)44:9<2078::AID-ART358>3.0.CO;2-J

10.1002/1096-9896(2000)9999:9999<::AID-PATH672>3.0.CO;2-W

La Flamme AC, 1999, The absence of IL‐6 does not affect Th2 cell development in vivo, but does lead to impaired proliferation, IL‐2 receptor expression, and B cell responses, J Immunol, 162, 5829, 10.4049/jimmunol.162.10.5829

10.4049/jimmunol.161.9.4652

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Wiley

Tập 54 Số 1

158-168

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