title: Signaling through the murine T cell receptor induces IL-17 production in the absence of costimulation, IL-23 or dendritic cells.
abstract: IL-17 (IL-17A or CTLA-8) is the founding member of a novel family of inflammatory cytokines, and emerging evidence indicates that it plays a central role in inflammation and autoimmunity. IL-17 is made primarily, if not exclusively by T cells, but relatively little is known about how its expression is regulated. In the present study, we examined the requirements and mechanisms for IL-17 expression in primary mouse lymphocytes. Like many cytokines, IL-17 is induced rapidly in primary T cells after stimulation of the T cell receptor (TCR) through CD3 crossinking. Surprisingly, however, the pattern of regulation of IL-17 is different in mice than in humans, because "costimulation" of T cells through CD28 only mildly enhanced IL-17 expression, whereas levels of IL-2 were dramatically enhanced. Similarly, several other costimulatory molecules such as ICOS, 4-1BB and CD40L exerted only very weak enhancing effects on IL-17 production. In agreement with other reports, IL-23 enhanced CD3-induced IL-17 expression. However, IL-17 production can occur autonomously in T cells, as neither dendritic cells nor IL-23 were necessary for promoting short-term production of IL-17. Finally, to begin to characterize the TCR-mediated signaling pathway(s) required for IL-17 production, we showed that IL-17 expression is sensitive to cyclosporin-A and MAPK inhibitors, suggesting the involvement of the calcineurin/NFAT and MAPK signaling pathways.
authors.affiliation: Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
authors.forename: Xikui K
authors.initials: XK
authors.lastname: Liu
authors.forename: James L
authors.initials: JL
authors.lastname: Clements
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003713:Dendritic Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D004791:Enzyme Inhibitors; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D016572:Cyclosporine; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin