IL-21-inducible TRPV6 is reduced in psoriatic skin

Abstract

Psoriasis is characterized by infiltration of inflammatory cells, hyperproliferation of epidermal cells and incomplete keratinocytes (KCs) differentiation (parakeratosis), impaired calcium gradient, and decreased skin barrier function. Interleukin-21 (IL-21), produced predominantly by multiple effector CD4+ T cell types and natural killer T cells, has pleiotropic actions such as induction of KC proliferation. In psoriasis, IL-21 mRNA and protein are highly expressed in the skin and peripheral blood mononuclear cells. IL-21 stimulates proliferation of both normal and psoriatic human KCs. So, a microarray analysis was performed in human KCs treated with IL-21 to find psoriasis-specific molecules, and transient receptor potential vanilloid 6 (TRPV6) was one of the increased genes. TRPV6 is a highly calcium-selective channel and its expression is mainly confined 2 to epithelial tissue of different organs such as kidney, testis, digestive tract, ovary and skin. Because psoriatic suprabasal layers display higher calcium concentration than normal skin, highly calcium-selective TRPV6 channel may be related to psoriasis. Moreover, TRPV6 is known to be important for the differentiation of KCs and the proliferation of epithelial cells. Therefore, TRPV6 could involve the defective differentiation and proliferation of psoriatic KCs. Although TRPV6 is known to be important in calcium-induced KC differentiation, its physiological function and mechanisms in the activation of KCs are unclear. Therefore, this study was investigated to determine whether TRPV6 plays a crucial role in psoriatic KCs. First, the differentiated model of KCs was established with treatment high calcium (1.2 mM). The RNA and protein levels of differentiation markers and TRPV6 were increased in accordance with differentiation of KCs, detected by real-time PCR and Western blot. However, immunohistochemical staining and real time PCR demonstrated that the mRNA and protein expressions of TRPV6 were decreased in psoriatic skin, suggesting that the decrease of TRPV6 might be related to reduced differentiation of KCs in psoriasis. To evaluate the role of TRPV6 on the proliferation of KCs in psoriasis, the effect of aTRPV6 inhibitor on the proliferation of KCs was evaluated by MTT assay. Contrary to the expectation, the reduced TRPV6 function in HaCaT cells caused by a TRPV6 inhibitor, LaCl3, did not significantly enhance the 3 proliferation of KCs. In addition, the co-treatment of IL-21 and LaCl3 did not affect the proliferation of KCs. The effect of LaCl3 in vitro could be different from the condition of decreased expression of TRPV6 in psoriatic KCs. Besides, the psoriatic KCs might not be fully reflected by the HaCaT KC cell line. In conclusion, TRPV6 was decreased in psoriatic epidermis, which might play a role in reduced differentiation of psoriatic KCs. However, the inhibition of TRPV6 function did not affect the proliferation of KC cells. Therefore, the role of TRPV6 in psoriatic KCs needs further elucidation.