Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation

Journal of Experimental Medicine - Tập 198 Số 12 - Trang 1951-1957 - 2003
Craig A. Murphy1, Claire L. Langrish2, Yi Chen2, Wendy M. Blumenschein3, Terrill K. McClanahan3, Robert A. Kastelein2, Jonathon D. Sedgwick2, J. Daniel2
1Discovery Research, DNAX Research Inc., Palo Alto, CA 94304, USA.
21Discovery Research, DNAX Research Inc., Palo Alto, CA 94304
32Experimental Pathology and Pharmacology, DNAX Research Inc., Palo Alto, CA 94304

Tóm tắt

Interleukin (IL) 23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 affects memory T cell and inflammatory macrophage function through engagement of a novel receptor (IL-23R) on these cells. Recent analysis of the contribution of IL-12 and IL-23 to central nervous system autoimmune inflammation demonstrated that IL-23 rather than IL-12 was the essential cytokine. Using gene-targeted mice lacking only IL-12 (p35−/−) or IL-23 (p19−/−), we show that the specific absence of IL-23 is protective, whereas loss of IL-12 exacerbates collagen-induced arthritis. IL-23 gene-targeted mice did not develop clinical signs of disease and were completely resistant to the development of joint and bone pathology. Resistance correlated with an absence of IL-17–producing CD4+ T cells despite normal induction of collagen-specific, interferon-γ–producing T helper 1 cells. In contrast, IL-12–deficient p35−/− mice developed more IL-17–producing CD4+ T cells, as well as elevated mRNA expression of proinflammatory tumor necrosis factor, IL-1β, IL-6, and IL-17 in affected tissues of diseased mice. The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.

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Journal of Experimental Medicine

Tập 198 Số 12

1951-1957

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