P38/ERK MAPK signaling pathways are involved in the regulation of filaggrin and involucrin by IL-17

Abstract

Atopic dermatitis (AD) is characterized by a defective skin barrier, which increases the penetration of allergens and pathogens through the skin. The role of interleukin (IL)-17, a pro-inflammatory cytokine, in the pathogenesis of AD remains to be elucidated. The present study aimed to examine the effects of IL-17 on skin barrier proteins in the HaCaT cell line. The expression levels of filaggrin (FLG) and involucrin (IVL) were evaluated by reverse transcription-quantitative polymerase chain reaction and western blot analyses of the HaCaT cells following IL-17 simulation. The role of IL-17 was further examined by using small molecule inhibitors of extracellular signal-regulated kinase (ERK) and P38. Treatment of the HaCaT cells with IL-17 resulted in reduced expression levels of FLG and IVL at the mRNA and protein levels. In addition, the gene expression levels of FLG and IVL were significantly reduced in the HaCaT cells by IL-4. Treatment with the mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD98059, significantly inhibited the effects of IL-17 on the gene and protein expression levels of FLG and IVL. Finally, the protein levels of phosphorylated ERK and P38 were significantly increased following IL-17 stimulation. Taken together, the results revealed that IL-17 reduced the expression of FLG and IVL in HaCaT cells, and this effect involved the P38/ERK MAPK signaling pathways.

Atopic Dermatitis Is an IL-13–Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis

“…Functions that were enriched among genes dysregulated in the direct AD versus psoriasis comparison included "carbohydrate derivative binding," "collagen metabolic process" ( Supplementary Table S5), among the significant functions encompassing AD-specific DEGs included activity and composition of "chloride channels," "regulation of fibroblast growth factor receptor signaling pathway," "regulation of macrophage activation," and "GABA ERK1/2 receptor activity" (Figure 2d). Interestingly, recent experimental data indicate that dysregulation of epidermal chloride channels (Seltmann et al, 2018), fibroblast growth factor receptor signaling (Sulcova et al, 2015), as well as P38/ERK MAPK signaling pathways (Tan et al, 2017), all impact epidermal barrier function and cutaneous homoeostasis, and might be involved in the pathogenesis of AD.…”

Effect of Hataedock Treatment on Epidermal Structure Maintenance through Intervention in the Endocannabinoid System

“…MAPKs, including ERK and JNK, are essential signals for the production of cytokines such as IL-4 and TNF-α [79] and regulate the inflammatory response through nuclear factorkappa B (NF-κB) activation [80]. IL-17, a proinflammatory cytokine, decreases the expression of filaggrin and involucrin in AD via the MAPKs signal pathway [81]. In our study, HTD also modulated the inflammatory response by blocking the MAPK signaling pathway by inhibiting the phosphorylation of ERK and JNK.…”

Immune mediators and therapies for pruritus in atopic dermatitis and psoriasis

“…The dimer can translocate to the nucleus and transcript target genes. 44 The elevation of IL-17 and subsequent downregulation of filaggrin in certain subtypes of AD may lead to skin barrier dysfunction in patients who don't carry filaggrin mutations. 30,38 While Th2 and Th22 immune response are predominant in many patients with AD, Th17 pathways are also activated in certain subtypes such as intrinsic, pediatric, and Asian-origin AD.…”

“…IL-17 is a pro-inflammatory cytokine, and it can downregulate the expression of filaggrin and involucrin, both of which are important skin barrier proteins, through the P38 and ERK pathways. 44 The elevation of IL-17 and subsequent downregulation of filaggrin in certain subtypes of AD may lead to skin barrier dysfunction in patients who don't carry filaggrin mutations. 45 Disruption of the skin barrier function can have several consequences in skin by potentially increasing allergen penetration and by provoking a barrier repair response that includes specific inflammatory responses.…”