Uncoupling melanogenesis from proliferation in epidermal melanocytes responding to stimulation with psoriasis-related proinflammatory cytokines

Background: Few studies have addressed the impact of the psoriasis-related proinflammatory cytokines on the proliferation and melanogenesis of melanocytes (MCs) in lesional psoriatic skin.

Objective: We investigated the effects of TNFα, IL17A, and IL8 on the proliferation and melanin synthesis of MCs.

Methods: Skin specimens were biopsied from patients with psoriasis vulgaris at the active stage, or from the tail skin of Dct-LacZ mice with imiquimod (IMQ)-induced psoriasiform dermatitis. Cultured keratinocytes (KCs), MCs, and human skin explants were used in this study. The numbers of MCs were measured via β-galactosidase staining, EdU incorporation and HMB45 immunohistochemical staining. The expression of human β-defensin 3 (hBD3) in KCs was silenced by siRNA, the conditioned medium (CM) from siRNA-transfected KCs was used to treat MCs, then followed by αMSH stimulation. The melanogenesis-related genes were examined by using qRT-PCR and western blotting.

Results: The increased number of MCs and decreased melanin content were highly relevant to the enhanced expression of IL8 and BD3 both in human psoriatic skin and in IMQ-treated mouse tail skin. IL8 expression in KCs and CXCR2 expression in MCs was significantly increased by IL17A and TNFα, the αMSH-induced upregulations of microphthalmia-associated transcription factor (MITF) and Tyrosinase in MCs were abrogated by the CM from hBD3-unsilenced KCs, but not from hBD3-silenced KCs.

Conclusion: Our results suggest the roles of IL8-CXCR2 activation in promoting MC proliferation and of BD3 upregulation in reducing melanogenesis. These findings have been implicated in the underlying mechanism that active psoriasis prefers hypopigmentation despite chronic inflammation.