Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.
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-1beta, 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.[1]References
- Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. Murphy, C.A., Langrish, C.L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R.A., Sedgwick, J.D., Cua, D.J. J. Exp. Med. (2003) [Pubmed]
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