Premium
IL ‐17A synergistically enhances TLR 3‐mediated IL ‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation
Author(s) -
Liu Shuangchun,
Wu Fei,
Wu Zongzhou,
Li Ying,
Zhang Shujie,
Yu Ning
Publication year - 2019
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13871
Subject(s) - proinflammatory cytokine , downregulation and upregulation , keratinocyte , p38 mitogen activated protein kinases , chemistry , inflammation , gene silencing , mapk/erk pathway , tumor necrosis factor alpha , microbiology and biotechnology , interleukin 17 , cytokine , cancer research , immunology , signal transduction , biology , biochemistry , in vitro , gene
Skin injury can trigger formation of new lesions in psoriasis (Koebner phenomenon). The mechanisms through which injury exacerbates psoriasis are unclear. During wound repair, epidermal keratinocytes are activated and produce abundant IL ‐36γ, further promoting the skin inflammation. IL ‐17A is the cornerstone cytokine in the pathogenesis of psoriasis. We sought to investigate the effects of IL ‐17A on injury‐induced keratinocyte activation and IL ‐36γ production. Here, we demonstrated that ds RNA released from necrotic keratinocytes induced the expression of IL ‐36γ. Silencing of TLR 3 by si RNA decreased the IL ‐36γ induction by necrotic keratinocyte supernatant. Co‐stimulation with ds RNA and IL ‐17A synergistically increased the expression of IL ‐36γ and other proinflammatory mediators ( CCL 20, CXCL 8, DEFB 4 and LCN 2) in keratinocytes. The synergistic effects were not dependent on TLR 3 upregulation, TNF receptor signalling and mRNA stabilization. Co‐stimulation with ds RNA and IL ‐17A resulted in an accumulation of IκBζ. The synergistic upregulation of IL ‐36γ and proinflammatory mediators were inhibited by IκBζ si RNA . Co‐stimulation with IL ‐17A and poly(I:C) markedly activated the p38 MAPK and NF ‐κB pathway, compared with poly(I:C). Blockade of p38 MAPK and NF ‐κB suppressed ds RNA / IL ‐17A–mediated IκBζ and IL ‐36γ induction. These findings demonstrated that IL ‐17A synergistically enhanced the ds RNA ‐mediated IL ‐36γ production through a p38 MAPK ‐, NF ‐κB–, and IκBζ‐dependent mechanism.