IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages

• Published in: The Journal of immunology (1950) 1998-04, Vol.160 (7), p.3513-3521
• Main Authors: Jovanovic, D V, Di Battista, J A, Martel-Pelletier, J, Jolicoeur, F C, He, Y, Zhang, M, Mineau, F, Pelletier, J P
• Format: Article
• Language: English
• Subjects: Adult; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Calcium - metabolism; Cells, Cultured; Cyclic AMP - agonists; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - biosynthesis; Dose-Response Relationship, Immunologic; Humans; Inflammation - drug therapy; Inflammation - immunology; Interleukin-1 - biosynthesis; Interleukin-1 - metabolism; Interleukin-10 - pharmacology; Interleukin-17; Interleukin-4 - pharmacology; Interleukins - pharmacology; Macrophage Activation; Macrophages - enzymology; Macrophages - immunology; Macrophages - metabolism; Middle Aged; NF-kappa B - biosynthesis; Protein Kinase Inhibitors; Time Factors; Transcription Factor AP-1 - biosynthesis; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.160.7.3513

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.