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

J Immunol. 1998 Apr 1;160(7):3513-21.

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.

MeSH terms

  • 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

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclic AMP Response Element-Binding Protein
  • Interleukin-1
  • Interleukin-17
  • Interleukins
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Cyclic AMP
  • Calcium