It is well known that psoriasis, an immunogenetic cutaneous disorder whose major pathogenic findings are epidermal hyperplasia and T-cell infiltration, is aggravated by psychological stresses. Although the exact mechanism is not yet clarified, antidromic secretion of neuropeptides by cutaneous nerve fibers is thought to be involved. In this study, we examined the effect and mechanism of vasoactive intestinal polypeptide (VIP), one of the major neuropeptides, on the proliferation of HaCaT cell which is a spontaneous, immortalized, human keratinocyte cell line. Twenty-four and 48 h after its addition, 1 pM to 100 nM of VIP increased the number of cells cultured with/without serum. We indirectly verified VIP(1)R on the surface of HaCaT cell based on the proliferative ability of various VIP families such as VIP, PACAP and secretin, and increased PKA level 30 min after stimulation. However, because H-89, a PKA inhibitor, did not inhibit the proliferative potential of VIP, its mitogenicity is not medicated through VIP(1)R. One nM VIP produced the TGF-alpha protein which is a strong mitogen of keratinocytes and increased in the psoriatic lesion 2.25 times more compared with the control. Genistein, a tyrosine kinase inhibitor, abrogated the mitogenic activity of VIP. Like VIP, VIP fragments, VIP(1-12) and VIP(10-28) also acted as a mitogen for HaCaT cells through the same mechanism. Collectively, our studies clearly show that VIP and its fragments stimulate keratinocyte growth, not through increased cAMP level, but through increased TGF-alpha protein production.
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