INTERLEUKIN-17 AND INTERFERON-GAMMA SYNERGIZE IN THE ENHANCEMENT OF PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN KERATINOCYTES

Keratinocytes are influenced by cytokines released by skin-infiltratin g T lymphocytes. IL-17 is produced by activated CD4(+) T cells and can stimulate epithelial cells. We investigated whether IL-17 could modul ate the cytokine production and cell-surface molecule expression of ke ratinocytes. The effects of IL-17 were compared with those of IFN-gamm a, which is also derived from activated T cells and is a strong stimul ator for keratinocytes. IL-17 enhanced the mRNA and protein production of the proinflammatory cytokines IL-6 and IL-8 in a concentration-dep endent way, and induced a weak expression of intercellular adhesion mo lecule (ICAM)-1 and HLA-DR. The production of IL-1 alpha and IL-15 was not altered. IFN-gamma augmented the production of IL-6, IL-8, and IL -15 and strongly induced both cell-surface molecules. IL-17 and IFN-ga mma showed marked synergism in the stimulation of IL-6 and IL-8 protei n secretion and, to a lesser extent, in the induction of ICAM-1 and HL A-DR expression. The majority of the CD4(+) and CD8(+) T cell clones d erived from lesional psoriatic skin expressed IL-17 mRNA, suggesting t hat skin-infiltrating T cells can produce this cytokine, This IL-17 mR NA expression was detectable in T helper cell type 1 and type 2 and di d not correlate with the IFN-gamma or IL-4 production. In addition, IL -17 mRNA is detectable in biopsies from lesional psoriatic skin, but n ot in nonlesional control biopsies. Our study indicates that IL-17 is a proinflammatory cytokine, which could amplify the development of cut aneous inflammation and may support the maintenance of chronic dermato ses, through stimulation of keratinocytes to augment their secretion o f proinflammatory cytokines.