Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells.

Abstract

IL-23 is regarded as a major pro-inflammatory mediator in autoimmune disease, a role which until recently was ascribed to its related cytokine IL-12. IL-23, an IL-12p40/p19 heterodimeric protein, binds to IL-12Rbeta1/IL-23R receptor complexes. Mice deficient for p19, p40 or IL-12Rbeta1 are resistant to experimental autoimmune encephalomyelitis or collagen-induced arthritis. Paradoxically, however, IL-12Rbeta2- and IL-12p35-deficient mice show remarkable increases in disease susceptibility, suggesting divergent roles of IL-23 and IL-12 in modulating inflammatory processes. IL-23 induces IL-17, which mediates inflammation and tissue remodeling, but the role of IL-12 in this respect remains unidentified. We investigated the roles of exogenous (recombinant) and endogenous (macrophage-derived) IL-12 and IL-23, on IL-17-induction in human T-cells. IL-23 enhanced IL-17 secretion, as did IL-2, IL-15, IL-18 and IL-21. In contrast, IL-12 mediated specific inhibition of IL-17 production. These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion. These data therefore extend previous reports that had indicated unique functions for IL-23 and IL-12 due to distinct receptor expression and signal transduction complexes, and provide novel insights into the regulation of immunity, inflammation and immunopathology.

• Authors: Marieke A Hoeve, Nigel D L Savage, Tjitske de Boer, Dennis M L Langenberg, René de Waal Malefyt, Tom H M Ottenhoff, Frank A W Verreck
• Journal: European journal of immunology (Eur J Immunol) Vol. 36 Issue 3 Pg. 661-70 (Mar 2006) ISSN: 0014-2980 [Print] Germany
• PMID: 16482511 (Publication Type: Journal Article)

Chemical References

• Cytokines
• IL23A protein, human
• Il23a protein, mouse
• Interleukin-23
• Interleukin-23 Subunit p19
• Interleukins
• Receptors, Interleukin
• Receptors, Interleukin-12
• Interleukin-12
• Collagen

Topics

• Animals
• Arthritis (chemically induced, immunology)
• Cells, Cultured
• Collagen (administration & dosage, adverse effects, immunology)
• Cytokines (pharmacology)
• Encephalomyelitis, Autoimmune, Experimental (genetics, immunology)
• Humans
• Inflammation (genetics, immunology)
• Interleukin-12 (deficiency, immunology, pharmacology)
• Interleukin-23
• Interleukin-23 Subunit p19
• Interleukins (deficiency, immunology, pharmacology)
• Mice
• Mice, Knockout
• Receptors, Interleukin (immunology)
• Receptors, Interleukin-12
• Signal Transduction (drug effects, immunology)
• T-Lymphocytes (cytology, immunology, metabolism)