title: IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages.
abstract: IL-17 is a newly described, T cell-derived cytokine with ill-defined physiologic properties. As such, we examined the release of proinflammatory mediators by human macrophages in response to recombinant human (rh) IL-17. IL-1beta and TNF-alpha expression and synthesis were up-regulated by rhIL-17 in a dose (ED50 was 50 +/- 9 ng/ml)- and time-dependent fashion, with cytokine accumulation reaching a zenith after 9 h. Release of IL-6, PGE2, IL-10, IL-12, IL-1R antagonist, and stromelysin was also stimulated by rhIL-17. IL-1beta and TNF-alpha mRNA expression levels were controlled by rhIL-17 in a complex manner with an initial 30-min inhibitory phase, and then up-regulation beginning at 1 h and reaching a plateau at about 3 h. The latter expression pattern closely mirrored the nuclear accumulation of the transcription factor nuclear factor-kappaB. cAMP mimetics isobutyl-1-methylxanthine (IBMX), forskolin, PGE2, and cholera toxin reversed rhIL-17-induced release of TNF-alpha, but had no consistent effect on induced IL-1beta synthesis. Induced release of TNF-alpha was also inhibited by serine/threonine protein kinase inhibitors KT-5720 (protein kinase A) and Calphostin C (protein kinase C), mitogen-activated protein kinase kinase inhibitor PD098059, and a nonspecific tyrosine kinase inhibitor, genistein. Calphostin C alone abrogated the rhIL-17-induced release of IL-1beta. The antiinflammatory cytokines IL-4 (p < 0.01) and IL-10 (p < 0.02) completely reversed rhIL-17-stimulated IL-1beta release, while IL-13 and TGF-beta2 were partially effective (59 and 43% diminution, respectively). 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-beta2 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.
authors.affiliation: Osteoarthritis Research Unit, Centre de recherche L.-C. Simard, University of Montreal, Quebec, Canada.
authors.forename: D V
authors.initials: DV
authors.lastname: Jovanovic
authors.forename: J A
authors.initials: JA
authors.lastname: Di Battista
authors.forename: J
authors.initials: J
authors.lastname: Martel-Pelletier
authors.forename: F C
authors.initials: FC
authors.lastname: Jolicoeur
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Mineau
authors.forename: J P
authors.initials: JP
authors.lastname: Pelletier
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology; D020381:Interleukin-17; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017362:Cyclic AMP Response Element-Binding Protein; D007375:Interleukin-1; D020381:Interleukin-17; D007378:Interleukins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D000242:Cyclic AMP; D002118:Calcium