IL-17 STIMULATES THE PRODUCTION AND EXPRESSION OF PROINFLAMMATORY CYTOKINES, IL-BETA AND TNF-ALPHA, BY HUMAN MACROPHAGES

IL-17 is a newly described, T cell-derived cytokine with ill-defined p hysiologic properties. As such, we examined the release of proinflamma tory mediators by human macrophages in response to recombinant human ( rh) IL-17. IL-1 beta and TNF-alpha expression and synthesis were up-re gulated by rhIL-17 in a dose (ED50 was 50 +/- 9 ng/ml)- and time-depen dent fashion, with cytokine accumulation reaching a zenith after 9 h. Release of IL-6, PGE(2), IL-10, IL-12, IL-1R antagonist, and stromelys in was also stimulated by rhIL-17. IL-1 beta and TNF-alpha mRNA expres sion levels were controlled by rhIL-17 in a complex manner with an ini tial 30-min inhibitory phase, and then up-regulation beginning at 1 h and reaching a plateau at about 3 h. The latter expression pattern clo sely mirrored the nuclear accumulation of the transcription factor nuc lear factor-kappa B. cAMP mimetics isobutyl-1-methylxanthine (IBMX), f orskolin, PGE(2), and cholera toxin reversed rhIL-17-induced release o f TNF-alpha, but had no consistent effect on induced IL-1 beta synthes is. Induced release of TNF-alpha was also inhibited by; serine/threoni ne protein kinase inhibitors KT-5720 (protein kinase A) and Calphostin C (protein kinase C), mitogen-activated protein kinase kinase inhibit or PD098059, and a nonspecific tyrosine kinase inhibitor, genistein. C alphostin C alone abrogated the rhIL-17-induced release of IL-1 beta. The antiinflammatory cytokines IL-4(p < 0.01) and IL-10 (p < 0.02) com pletely reversed rhIL-17-stimulated IL-1 beta release, while IL-13 and TGF-beta(2) were partially effective (59 and 43% diminution, respecti vely). IL-10 exerted a significant suppressive effect on IL-17-induced TNF-alpha release (99%, p < 0.02), while the inhibitory effects of IL -4, IL-13, and TGF-beta(2) on TNF-alpha secretion were partial (48, 10 , and 23%, respectively). The data suggest a pivotal role for IL-17 in initiating and/or sustaining an inflammatory response.