The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor

Nerve growth factor is an essential neurotrophic factor required for the gr owth and maintenance of cutaneous sensory nerves. In the skin, keratinocyte s are a significant source of nerve growth factor; however, the regulation of cutaneous nerve growth factor production still remains to be fully under stood. In this study we tested the hypothesis that neuropeptides released b y cutaneous sensory nerves have the capacity to modulate directly the expre ssion of keratinocyte nerve growth factor, which would have important impli cations for the maintenance and repair of nerves in the skin. In order to a ddress this question experimentally we examined the effect of the neuropept ides, substance P and neurokinin A, on nerve growth factor expression in hu man keratinocytes and the murine keratinocyte PAM 212 cell line by quantita tive reverse transcriptase-polymerase chain reaction, enzyme-linked immunos orbent assay, and the PC-12 nerve growth factor bioassay. The results of th ese studies indicated that substance P and neurokinin A can directly induce nerve growth factor mRNA expression and the secretion of bioactive nerve g rowth factor protein in both human and murine keratinocytes. The specificit y of these responses was demonstrated using neuropeptide receptor antagonis ts and nerve growth factor blocking antibodies. Additional studies also dem onstrated a significant in vivo upregulation of keratinocyte nerve growth f actor expression in murine epidermis after the topical application of the n europeptide releasing agent capsaicin. This is the first report demonstrati ng the induction of cutaneous nerve growth factor by sensory nerve-derived neuropeptides such as substance P and neurokinin A. This direct effect of t he neurosensory system on keratinocyte nerve growth factor production may h ave important consequences for the maintenance and regeneration of cutaneou s nerves in normal skin and during inflammation and wound healing.