Pro‐inflammatory cytokine IL‐6 regulates LMO4 expression in psoriatic keratinocytes via AKT/STAT3 pathway

Abstract

AbstractThe transcription factor LIM‐only protein 4 (LMO4) is overexpressed in the psoriatic epidermis and regulates keratinocyte proliferation and differentiation. High LMO4 expression levels are induced by interleukin‐23 (IL‐23) to activate the AKT/STAT3 signaling pathway. Interleukin‐6 (IL‐6) is mainly involved in regulating T cell functions and development in patients with psoriasis. However, whether LMO4 expression is regulated by IL‐6 remains unclear. Therefore, the purpose of this study is to explore the role and molecular mechanisms of IL‐6 in regulating LMO4 expression. The interleukin‐6 (IL‐6) levels in human plasma were determined using a chemiluminescence immunoassay system. A psoriasis‐like mouse model was established using imiquimod induction. Epidermal keratinocytes (HaCaT) were cultured in defined keratinocyte‐serum‐free medium and stimulated by IL‐6 alone or with inhibitors. The proteins of interest were detected using western blot analysis, immunofluorescence, and immunohistochemistry. The 5‐ethynyl‐2′‐deoxyuridine assay was used to detect cell proliferation. The results revealed that IL‐6 levels were markedly increased in the plasma of patients with psoriasis, compared to healthy control. The high expression of LMO4 was consistent with high levels of IL‐6, p‐AKT, and p‐STAT3 in the lesions of both psoriasis patients and imiquimod‐induced psoriasis‐like mice. IL‐6 activates the AKT/STAT3 signaling pathway, followed by LMO4 high‐expression in HaCaT cells. IL‐6 induces HaCaT proliferation and differentiation via AKT/STAT3 signaling pathway activation. We think that the high expression of LMO4 in psoriatic keratinocytes requires IL‐6 to activate the AKT/STAT3 signaling pathway and leads to epidermal keratinocytes abnormal proliferation and differentiation.