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Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.

Abstract
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.
AuthorsCraig A Murphy, Claire L Langrish, Yi Chen, Wendy Blumenschein, Terrill McClanahan, Robert A Kastelein, Jonathon D Sedgwick, Daniel J Cua
JournalThe Journal of experimental medicine (J Exp Med) Vol. 198 Issue 12 Pg. 1951-7 (Dec 15 2003) ISSN: 0022-1007 [Print] United States
PMID14662908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Collagen Type II
  • Il23a protein, mouse
  • Interleukin-17
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma
Topics
  • Animals
  • Arthritis, Experimental (etiology, immunology, therapy)
  • Collagen Type II (immunology)
  • Female
  • Interferon-gamma (biosynthesis)
  • Interleukin-12 (physiology)
  • Interleukin-17 (biosynthesis)
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins (physiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes (immunology)
  • Tumor Necrosis Factor-alpha (biosynthesis)

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