In:
The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 223.7-223.7
Kurzfassung:
Rho-associated kinase 2 (ROCK2) was recently shown to be implicated in regulation of IL-17 and IL-21 secretion in both mice and humans via down-regulation of STAT3 phosphorylation and subsequent transcription activity. Here we report that the ROCK2, but not ROCK1 protein binds phosphorylated-STAT3 (pSTAT3) in both cytoplasmic and nuclear compartments in human CD4+ T cells during T helper 17 (TH17)-skewing activation. The interaction of ROCK2 with pSTAT3 was partially abrogated by treatment of cells with selective ROCK2 inhibitor suggesting that ROCK2 kinase activity is required for formation of JAK-STAT complex and STAT3 phosphorylation. Further analysis by chromatin-immunoprecipitation sequencing (ChIP-seq) revealed that ROCK2 binding is significantly enriched toward promoter regions and peaks at transcription start sites (TSS) relative to genomic DNA. Moreover, 60–70% of ROCK2 and STAT3 peaks are overlapped genome-wide and co-localized to several key genes that control TH17 and T follicular helper (TFH) cell functions. Specifically, the binding of ROCK2 and STAT3 to the IRF4 and Bcl6 genes was validated by ChIP-qPCR analysis performed in human CD4+ T cells activated by TH17-skewing conditions. Finally, siRNA-mediated inhibition of STAT3 attenuated ROCK2 binding to the IRF4 and Bcl6 promoters indicating the critical role of STAT3 in the recruitment of ROCK2 to chromatin and ROCK2-mediated regulation of TH17/TFH gene transcription. Together, the present work provides previously unidentified insights into the molecular mechanism of specific involvement of ROCK2 isoform in regulating STAT3 phosphorylation and transcriptional activity in TH17-driven autoimmune responses.
Materialart:
Online-Ressource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.198.Supp.223.7
Sprache:
Englisch
Verlag:
The American Association of Immunologists
Publikationsdatum:
2017
ZDB Id:
1475085-5
