IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: Synergistic or antagonist effects with IFN-gamma and TNF-alpha

IL-17 is a novel T cell-derived cytokine that can regulate the functions of a variety of cell types. In this study, we investigated whether hapten-spe cific T cells isolated from patients with allergic contact dermatitis (ACD) to nickel produce IL-17 and the effects of IL-17 alone or in combination w ith IFN-gamma or TNF-alpha on the immune activation of keratinocytes. Skin affected with ACD to nickel and skin-derived, nickel-specific CD4(+) T cell lines expressed IFN-gamma, TNF-alpha, and IL-17 mRNAs. Four of seven nicke l-specific CD4(+) T cell clones positive for the skin-homing receptor, cuta neous lymphocyte-associated Ag, were shown to corelease IL-17, IFN-gamma, a nd TNF-alpha. In contrast, two nickel-specific CD8(+) T cell clones failed to synthesize IL-17. Normal human keratinocytes were found to express const itutively the IL-17 receptor gene, IL-17 specifically and dose-dependently augmented IFN-gamma-induced ICAM-1 expression on keratinocytes at both the mRNA and the protein level, whereas HLA-DR, MHC class I, and CD40 levels we re not modulated by IL-17, On the other hand, IL-17 alone did not affect IC AM-1 or enhance TNF-alpha-induced ICAM-1, In addition, IL-17, both directly and in synergism with IFN-gamma and/or TNF-alpha, stimulated synthesis and release of IL-8 by keratinocytes, In contrast, IFN-gamma- and TNF-alpha-in duced production of RANTES was markedly inhibited by IL-17, and the synthes is of macrophage chemotactic protein 1 was not changed. Taken together, the results suggest that IL-17 is an important player of T cell-mediated skin immune responses, with synergistic or antagonist effects on IFN-gamma- and TNF-alpha-stimulated keratinocyte activation.