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Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF‐α and PGE2
Author(s) -
Hu Yang,
ParkMin KyungHyun,
Yarilina Anna,
Ivashkiv Lionel B.
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0107040
Subject(s) - stat1 , biology , irf1 , autocrine signalling , microbiology and biotechnology , phosphorylation , tyrosine phosphorylation , signal transduction , jak stat signaling pathway , paracrine signalling , stat4 , tumor necrosis factor alpha , stat3 , stat , transcription factor , cell culture , immunology , gene , receptor , receptor tyrosine kinase , biochemistry , genetics
Maturation of dendritic cells (DCs) by TLR ligands induces expression of IFN‐β and autocrine activation of IFN‐inducible Stat1‐dependent genes important for DC function. In this study, we analyzed the regulation of STAT signaling during maturation of human DCs by TNF‐α and PGE2, which induced maturation of human DCs comparably with LPS but did not induce detectable IFN‐β production or Stat1 tyrosine phosphorylation. Consistent with these results, TNF‐α and PGE2 did not induce Stat1 DNA binding to a standard Stat1‐binding oligonucleotide. Instead, TNF‐α and PGE2 increased Stat1 serine phosphorylation and Stat4 tyrosine phosphorylation and activated expression of the NF‐κB and Stat1 target gene IFN regulatory factor 1 ( IRF1 ), which contributes to IFN responses. TNF‐α and PGE2 induced a complex that bound an oligonucleotide derived from the IRF1 promoter that contains a STAT‐binding sequence embedded in a larger palindromic sequence, and this complex was recognized by Stat1 antibodies. These results suggest that TNF‐α and PGE2 activate STAT‐mediated components of human DC maturation by alternative pathways to the IFN‐β‐mediated autocrine loop used by TLRs.