CGRP, PACAP, and VIP modulate langerhans cell function by inhibiting NF-κB activation

The neuropeptides calcitonin gene- related peptide ( CGRP), pituitary adenylate cyclase- activating polypeptide ( PACAP), and vasoactive intestinal peptide ( VIP) suppress Langerhans cell ( LC) antigen presentation and modulate cytokine production. We have tested the hypothesis that these neuropeptides ( NP) inhibit LC function by modulating activation of NF-kappa B. Lipopolysaccharide ( LPS) activates NF-kappa B in both a LC- like cell line (XS52) and epidermal LC enriched to similar to 95% and this effect is inhibited by each of the NP. Furthermore, CGRP, PACAP, and VIP suppress phosphorylation of I kappa B kinase beta(P-IKK beta), prevent degradation of the I kappa B alpha, and inhibit activation of NF-kappa B. Thus, these NP modulate LC function by reducing NF-kappa B activation. Bay 11- 7085, an inhibitor of IKK, reduced tumor necrosis factor-alpha ( TNF alpha) production from LPS- stimulated XS52 cells and inhibited the ability of LC to present antigen to a T- cell clone in vitro. Each NP also inhibited LPS- induced secretion of TNF alpha by XS52 cells and LC enriched to similar to 95% homogeneity. We suggest that the inhibitory activities of CGRP, PACAP, and VIP on LC function are mediated, at least in part, by inhibition of P- IKK beta, which prevents I kappa B alpha degradation and activation of NF-kappa B. Modulation of this signaling pathway may be useful for therapeutic modulation of immunity in the skin.