IL-6 Up-Regulates Expression of LIM-Domain Only Protein 4 in Psoriatic Keratinocytes through Activation of the MEK/ERK/NF-κB Pathway

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by the activation of keratinocytes and the infiltration of immune cells. Overexpression of the transcription factor LIM-domain only protein 4 (LMO4) promoted by interleukin-23 (IL-23) has critical roles in regulating the proliferation and differentiation of psoriatic keratinocytes. IL-6, an autocrine cytokine in psoriatic epidermis, is a key mediator of IL-23/T helper (Th17)-driven cutaneous inflammation. However, little is known about how IL-6 regulates the upregulation of LMO4 expression in psoriatic lesions. In this study, human immortalized keratinocyte (HaCaT) cells, clinical biopsy specimens, and an animal model of psoriasis induced by imiquimod cream were used to investigate the role of IL-6 in the regulation of keratinocyte proliferation and differentiation. We found that IL-6 and LMO4 were abnormally expressed in the psoriatic epidermis. IL-6 up-regulates the expression of LMO4 and promotes keratinocyte proliferation and differentiation. Furthermore, in vitro and in vivo studies showed that IL-6 upregulates LMO4 expression by activating the MEK/ERK/NF-κB signaling pathway. These results suggest that IL-6 can activate the NF-κB signaling pathway, upregulate the expression of LMO4, lead to abnormal proliferation and differentiation of keratinocytes, and promote the occurrence and development of psoriasis.