IL-19 may aggravate atopic dermatitis by enhancing the role of IL-4/IL-13 in downregulating keratinocyte barrier proteins and upregulating the secretion of proinflammatory cytokines

Abstract

Abstract Atopic dermatitis (AD) is a relapsing inflammatory skin disorder, with characteristic T helper 2 (Th2)-based immune dysregulation and epidermal barrier function defect. In AD, keratinocyte plays a critical role in maintaining skin integrity and immune homeostasis. Interleukin (IL)-19 is a member of the IL-10 cytokine family. It can be secreted by and act on keratinocytes. Although it has been demonstrated that increased IL-19 in AD patients’ lesions and serum is positively correlated with the severity of AD, the role of IL-19 in the regulation of the epidermal barrier and immune homeostasis of keratinocytes remains unclear. Thus, we aim to investigate the effect of IL-19 on the production of epidermal barrier related proteins and proinflammatory cytokines in keratinocytes, and the synergistic effect of IL-19 with IL-4/IL-13 in vitro experiment. In this study, barrier related proteins (filaggrin/FLG, loricrin/LOR, keratin-10), epithelium-derived cytokines (thymic stromal lymphopoietin/TSLP, IL-33, IL-25), IL-19 and the phosphorylation level of STAT3 and STAT6 were measured in HaCaT cells by RT-PCR and/or western blot before and after stimulated with IL-4/IL-13 with or without different concentrations of IL-19. The changes of IL-19 levels in HaCaT cells after stimulation with house dust mite (HDM) or staphylococcal enterotoxin type B (SEB) were also examined. We found that IL-19 could promote the production of TSLP in keratinocytes, but reduce the expression levels of LOR and keratin-10. Meanwhile, IL-19 significantly enhanced the effects of IL-4/IL-13 on keratinocytes, including inducing the expression of IL-19 and epithelial derived cytokines and inhibiting the expression of barrier proteins. These enhanced effects were accompanied by increased phosphorylation of STAT3 and STAT6, but no change in the expression level of IL-4/13 receptor. In addition, HDM but not SEB can induce keratinocytes to secrete IL-19. Taken together, IL-19 can enhance the effect of IL-4 / IL-13 on keratinocytes in vitro, and may play an important role in the pathogenesis and progression of AD.