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.
|
Authors | Craig A Murphy, Claire L Langrish, Yi Chen, Wendy Blumenschein, Terrill McClanahan, Robert A Kastelein, Jonathon D Sedgwick, Daniel J Cua |
Journal | The Journal of experimental medicine
(J Exp Med)
Vol. 198
Issue 12
Pg. 1951-7
(Dec 15 2003)
ISSN: 0022-1007 [Print] United States |
PMID | 14662908
(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)
|