The Journal of Experimental Medicine
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Published online 8 December 2003 doi:10.1084/jem.20030896
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© Rockefeller University Press, 0022-1007/2003/12/1951 $5.00
The Journal of Experimental Medicine, Volume 198, Number 12, 1951-1957

Brief Definitive Report

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

Craig A. Murphy1, Claire L. Langrish1, Yi Chen1, Wendy Blumenschein2, Terrill McClanahan2, Robert A. Kastelein1, Jonathon D. Sedgwick1 and Daniel J. Cua1

1 Discovery Research, DNAX Research Inc., Palo Alto, CA 94304
2 Experimental Pathology and Pharmacology, DNAX Research Inc., Palo Alto, CA 94304

Address correspondence to Daniel J. Cua, 901 California Ave., Palo Alto, CA 94304. Phone: (650) 496-1261; Fax: (650) 496-1200; email: daniel.cua{at}dnax.org; or Jonathon D. Sedgwick. Phone: (650) 496-1248; email: jonathon.sedgwick{at}dnax.org

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-{gamma}–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-1ß, 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.

Key Words: rheumatoid arthritis • collagen-induced arthritis • IL-23 gene–deficient mice • IL-17 • IFN-{gamma}

C.A. Murphy and C.L. Langrish contributed equally to this work.


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