Interleukin-6 and Oncostatin M in experimental joint pathology.
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KUN Katholieke Universiteit Nijmegen, 02 november 2004
Promotor : Berg, W.B. van den Co-promotor : Loo, F.A.J. van de
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SubjectUMCN 4.2: Chronic inflammation and autoimmunity
Elevated levels of cytokines have been found in affected joints of people suffering from osteoarthritis (OA) or rheumatoid arthritis. One of the cytokines that is found in these joints is Interleukin-6 (IL-6). IL-6 is a multifunctional cytokine that has both good and bad properties with regard to inflammation. In the present thesis the role of IL-6 and its family member Oncostatin M (OSM) in joint pathology was investigated in experimental models with wild-type and IL-6 deficient (IL-6-/-) mice. Old wild-type and IL-6-/- mice were compared for signs of spontaneous OA. Male, but not female, IL-6-/- mice developed significantly more OA than wild-type mice. Bone mineralization and proteoglycan production were reduced in IL-6-/- males. Together these data point at a positive role for IL-6 in preventing OA, at least in males. In different arthritis models, it was found that IL-6-/- mice develop an acute joint inflammation but this does not develop in chronic inflammation. Transfer of antigen-specific wild-type lymph node cells increased the acute inflammation but did not lead to chronicity in IL-6-/- mice. Similarly, IL-6-/- mice with irritant-induced zymosan-induced arthritis (ZIA) did not develop chronic inflammation. Together these models indicate an important role for IL-6 in propagation of joint inflammation, potentially independent of its role in immunity. Further research on the ZIA showed impaired activation of the transcription factors STAT1 and STAT3 in IL-6-/- mice. Exacerbation of ZIA in STAT1 deficient mice suggests that STAT1 and STAT3 play opposite roles in control and development of joint inflammation. The role of OSM in joint pathology was investigated by adenoviral over-expression of murine OSM. OSM induced joint inflammation, bone opposition, proteoglycan depletion and growth plate damage independent of IL-6, TNF-a or iNOS. Finally, an IL-6 promoter-based adenoviral system showed feasibility of disease-regulated transgene expression in the joint.
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