Substance P enhances the production of interferon-induced protein of 10 kDa by human keratinocytes in synergy with interferon-γ

A neuropeptide substance P is related to skin inflammation. Interferon-induced protein of 10 kDa (IP-10) chemoattracts T helper 1 cells, and interferon-induced protein of 10 kDa production by keratinocytes is enhanced in inflammatory skin diseases such as psoriasis. We examined the in vitro effects of substance P on interferon-induced protein of 10 kDa production by human keratinocytes. Though substance P alone did not induce interferon-induced protein of 10 kDa production, it enhanced interferon-induced protein of 10 kDa secretion, mRNA expression, and promoter activity induced by suboptimal concentrations of interferon-gamma. Interferon-stimulated response element and two nuclear factor-kappaB sites on interferon-induced protein of 10 kDa promoter were responsible for the enhancement by substance P. Substance P alone enhanced transcriptional activity and transcription factor binding through the two nuclear factor-kappaB sites, whereas it did not alter interferon-gamma-induced transcriptional activity and transcription factor binding through interferon-stimulated response element. The effects of substance P on interferon-induced protein of 10 kDa production and nuclear factor-kappaB activation were inhibited by neurokinin-1 receptor antagonist, phospholipase C inhibitor, intracellular Ca2+ chelator, and anti-oxidant. These results suggest that substance P may induce nuclear factor-kappaB activation and interferon-induced protein of 10 kDa production in synergy with interferon-gamma via neurokinin-1 receptor on keratinocytes. These effects of substance P may be mediated via phospholipase C activation, intra-cellular Ca2+ signal, and reactive oxygen intermediates.