Abstract
Cytokine IL-17A (IL-17) acts on various cell types, including epidermal keratinocytes, and induces antimicrobial peptide and chemokine production to elicit antibacterial and antifungal defense responses. Excess IL-17 leads to inflammatory skin diseases such as psoriasis. The IκB family protein IκB-ζ mediates IL-17-induced responses. However, the mechanism controlling IκB-ζ expression in IL-17-stimulated cells remains elusive. In this study, we showed that JAK kinase TYK2 positively regulates IL-17-induced IκB-ζ expression. TYK2-deficient mice showed reduced inflammation and concomitant reduction of IκB-ζ mRNA compared with wild-type mice in imiquimod-induced skin inflammation. The analysis of the IκB-ζ promoter activity using human cell lines (HaCaT and HeLa) revealed that catalytic activity of TYK2 and its substrate transcription factor STAT3, but not IL-17, is required for IκB-ζ promoter activity. In contrast, IL-17-induced signaling, which did not activate STAT3, posttranscriptionally stabilized IκB-ζ mRNA via its 3'-untranslated region. IL-17 signaling protein ACT1 was required to counteract constitutive IκB-ζ mRNA degradation by RNase Regnase-1. These results suggested that transcriptional activation by TYK2-STAT3 pathway and mRNA stabilization by IL-17-mediated signals act separately from each other but complementarily to achieve IκB-ζ induction. Therefore, JAK/TYK2 inhibition might be of significance in regulation of IL-17-induced inflammatory reactions.
Highlights
Psoriasis is an immune-related chronic skin disease characterized by erythematous, scaly, sharply demarcated plaques
Involvement of Tyrosine kinase-2 (TYK2) in Nfkbiz expression in IMQ-induced psoriasis-like skin inflammation We investigated the role of TYK2 in IkB-z gene expression in skin inflammation using TYK2-deficient mice
The level of Il17a mRNA in the IMQ-treated ears of TYK2-deficient mice was lower than in those of WT mice but was still firmly detected (Fig. 1B). These results suggested that TYK2 deficiency resulted in the decreased induction of IL-17–responding as well as IL-17 genes in the IMQ-treated lesions
Summary
Psoriasis is an immune-related chronic skin disease characterized by erythematous, scaly, sharply demarcated plaques. IL-17A (IL-17) is a key inflammatory cytokine present within psoriasis lesions [2,3,4] and is mainly produced from immune cells, such as activated T cells. IL-17 has a direct effect on the induction of genes expressed by keratinocytes involved in innate immune defense and a range of CXC chemokines that regulate immune cell trafficking [5,6,7]. This immune cell feedback has been considered to amplify and prolong psoriatic inflammation [2, 8].
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