Neuropeptides modulate leukotriene B4 mitogenicity toward cultured human keratinocytes

Neuropeptides released in skin from nerve fibers may interact with endogenous growth factors (or other mitogenic agents) to induce psoriasis lesions characterized by proliferating epidermal keratinocytes. The mitogenic effects of two neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), on human adult and newborn keratinocytes were observed in the presence or absence of leukotriene B4 (LTB4) and leukotriene C4 (LTC4). In the presence of SP or VIP, LTB4 (but not LTC4) demonstrated substantial increase in thymidine incorporation into DNA, which was confirmed by cell-growth observations using the hexosaminidase assay. In the absence of either neuropeptide, LTB4 had only marginal effects, especially with adult (but not newborn) keratinocytes. With adult keratinocytes, LTB4 (but not LTC4) demonstrated synergy with both SP and VIP. VIP was mitogenic to keratinocytes at concentrations as low as 10(-12)M and exhibited a different dose-response curve depending on whether adult or newborn keratinocytes were used. The mitogenic effects of SP were abrogated by the SP antagonist spantide and those of VIP by the VIP antagonist [Ac-Tyr1, D-Phe2] growth-hormone-releasing factor (1-29) amide. This study suggests that the mitogenic effects of LTB4, which are elevated in psoriatic lesions, may be enhanced by the presence of neuropeptides, especially VIP. These effects can be reversed by antagonists that may have potential as drugs for the disease.