Substance P induction of murine keratinocyte PAM 212 interleukin 1 production is mediated by the neurokinin 2 receptor (NK-2R)

The neurological system plays an important rule in modulating some inflamma tory skin diseases. Neuro-cutaneous interactions may be mediated by the rel ease of neuropeptides such as substance P (SP) which activate immunocompete nt cells in the skin by binding to high affinity neurokinin receptors (NKR) . Since epidermal keratinocytes produce a variety of cytokines and are inti mately associated with cutaneous sensory fibers, we tested the ability of t hese cells to participate in the cutaneous neuroimmune system by the secret ion of potent cytokines such as interleukin 1 (IL-1) in response to release d SP RT-PCR studies demonstrated that cultured PAM 212 murine keratinocytes expressed mRNA for NK-2R but not NK-IR. Correspondingly, the addition of S P to these cells resulted in a rapid increase in intracellular Ca2+ levels that could be specifically blocked by an NK-2R antagonist. NK-2R was also s hown in normal mouse epidermis by immunohistochemistry. SP augmented the ex pression of PAM 212 keratinocyte IL-1 alpha mRNA in a dose and time depende nt manner and this induction was inhibited by an NK-2R antagonist. Secretio n of bioactive IL-1 alpha by the PAM 212 keratinocytes was likewise stimula ted by SP in a dose dependent manner. These data support the hypothesis tha t SP released from cutaneous sensory nerves contributes to neuroimmune infl ammatory responses in the skin by modulating the expression and release of cytokines from epidermal keratinocytes.