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IκB-ζ Expression Requires Both TYK2/STAT3 Activity and IL-17–Regulated mRNA Stabilization
- Source :
- ImmunoHorizons. 3(5):172-185
- Publication Year :
- 2019
- Publisher :
- The American Association of Immunologists, 2019.
-
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.
- Subjects :
- Keratinocytes
STAT3 Transcription Factor
Chemokine
medicine.medical_treatment
RNA Stability
Immunology
Gene Knockout Techniques
Mice
Ribonucleases
medicine
Immunology and Allergy
Animals
Humans
Psoriasis
RNA, Messenger
STAT3
Transcription factor
3' Untranslated Regions
Protein Kinase Inhibitors
Adaptor Proteins, Signal Transducing
Mice, Knockout
TYK2 Kinase
Mice, Inbred BALB C
biology
Chemistry
Interleukin-17
General Medicine
MRNA stabilization
Cell biology
HaCaT
Disease Models, Animal
Cytokine
Tyrosine kinase 2
biology.protein
Janus kinase
HeLa Cells
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 25737732
- Volume :
- 3
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- ImmunoHorizons
- Accession number :
- edsair.doi.dedup.....13e7d07d45c1a730987f4f202a5d9089