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

By C. Murphy, C. Langrish, Yi Chen, W. Blumenschein, T. Mcclanahan, R. Kastelein, J. Sedgwick, D. Cua. Journal of Experimental Medicine, 2003

1,857 citations recorded by the source corpus.

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.

Subfields: Dermatology, Immunology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/2c8c6d3f4b4522951ff0c0ec174923e4405a6b8a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Dermatology

1. D. Cua
2. C. Weaver
3. Christopher A. Hunter
4. V. Kuchroo
5. Y. Iwakura
6. H. Ishigame
7. Dan R. Littman
8. E. Bettelli

In Immunology

1. D. Cua
2. Dan R. Littman
3. R. Flavell
4. C. Dong
5. V. Kuchroo
6. Ming O. Li
7. M. Karin
8. C. Weaver

In Pathology and Forensic Medicine

1. D. Cua
2. V. Kuchroo
3. Dan R. Littman
4. C. Weaver
5. Y. Iwakura
6. L. Harrington
7. Paul R. Mangan
8. E. Bettelli

Citations in the corpus

• New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions (2005, background): “Similarly, studies of CIA revealed that the absence of IL-12p35 leads to exacerbated arthritis, whereas IL-23-deficient animals are resistant to the development of bone and joint patholog”
• IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses (2011, background): “Both the T H 1 subset and the T H 17 subset promote cellular immune function and can cause inflammation and autoimmune diseases, such as inflammatory bowel disease and collagen-induce arthriti”
• MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development (2010, background): “Subsequent studies demonstrated that inhibition of IL-17 in mice can ameliorate several autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), and inflammatory bowel dis- ease (IBD) (Ivanov et al., 2006; Komiyama et al., 2006; Murphy et al.,”
• IL-17 Production Is Dominated by γδ T Cells rather than CD4 T Cells during Mycobacterium tuberculosis Infection1 (2006, background): “IL-23 also promotes IL-17-mediated chronic inflammation in collagen-induced arthritis (2).”
• Cytokines in the pathogenesis of rheumatoid arthritis (2007, neutral): “This model is supported by the observation of accelerated collagen-induced arthritis (CIA) in mice that lack the T H 1-cell-associated genes Ifng , Ifngr or Il12p35 (Ref”
• Innate IL-17-producing cells: the sentinels of the immune system (2010, background): “Evidence for innate sources of IL-17 Following the discovery that IL-23 promotes the secretion of IL-17 by memory CD4 + T cell”
• Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system (2006, background): “These 'T H -17' lymphocytes have been suggested to be mediators of the inflammation associated with several autoimmune diseases, including experimental autoimmune encephalitis (EAE) and collagen-induced arthriti”
• IL-17 and Th17 Cells. (2009, background): “163 IL-21 pathogenic Blockade of IL-21 signaling by administration of IL-21R-Fc fusion protein attenuated CIA.”