IL-17 Stimulates the Production and Expression of Proinflammatory Cytokines, IL-β and TNF-α, by Human Macrophages
Open Access
- 1 April 1998
- journal article
- Published by Oxford University Press (OUP) in The Journal of Immunology
- Vol. 160 (7) , 3513-3521
- https://doi.org/10.4049/jimmunol.160.7.3513
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-1β and TNF-α 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-1β and TNF-α 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-κB. cAMP mimetics isobutyl-1-methylxanthine (IBMX), forskolin, PGE2, and cholera toxin reversed rhIL-17-induced release of TNF-α, but had no consistent effect on induced IL-1β synthesis. Induced release of TNF-α 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-1β. The antiinflammatory cytokines IL-4 (p < 0.01) and IL-10 (p < 0.02) completely reversed rhIL-17-stimulated IL-1β release, while IL-13 and TGF-β2 were partially effective (59 and 43% diminution, respectively). IL-10 exerted a significant suppressive effect on IL-17-induced TNF-α release (99%, p < 0.02), while the inhibitory effects of IL-4, IL-13, and TGF-β2 on TNF-α 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.Keywords
This publication has 62 references indexed in Scilit:
- PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in VivoJournal of Biological Chemistry, 1995
- Structure, Regulation and Function of NF-kappaBAnnual Review of Cell Biology, 1994
- Protein kinase C - a question of specificityTrends in Biochemical Sciences, 1994
- Modulation of TNFα and IL-1β from endotoxin-stimulated monocytes by selective PDE isozyme inhibitorsInflammation Research, 1993
- Inhibition of protein kinase C by calphostin C is light-dependentBiochemical and Biophysical Research Communications, 1991
- The role of IL-10 in crossregulation of TH1 and TH2 responsesImmunology Today, 1991
- Biologically active products of stimulated liver macrophages (Kupffer cells)European Journal of Biochemistry, 1990
- Molecular mechanisms of signal transduction in macrophagesImmunology Today, 1987
- Cyclic AMP levels and their regulation by prostaglandins in peritoneal macrophages of rats and humansInternational Journal of Immunopharmacology, 1984
- Immunomodulatory-antiinflammatory functions of E-type prostaglandins. Minireview with emphasis on macrophage-mediated effectsInternational Journal of Immunopharmacology, 1982