Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells.
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.
Hoeve
Marieke A
MA
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Savage
Nigel D L
ND
de Boer
Tjitske
T
Langenberg
Dennis M L
DM
de Waal Malefyt
René
R
Ottenhoff
Tom H M
TH
Verreck
Frank A W
FA
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology; D002478:Cells, Cultured; D003094:Collagen / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology* / Q000494:pharmacology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000172:deficiency / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000276:immunology; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D003094:Collagen