Published online before print August 4, 2008
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and PGE2
,3
* Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA; and
Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA
3 Correspondence: Hospital for Special Surgery, 535 East 70th St., New York, NY 10021, USA. E-mail: IvashkivL{at}HSS.edu
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-
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- and PGE2 did not induce Stat1 DNA binding to a standard Stat1-binding oligonucleotide. Instead, TNF- and PGE2 increased Stat1 serine phosphorylation and Stat4 tyrosine phosphorylation and activated expression of the NF-
B and Stat1 target gene IFN regulatory factor 1 (IRF1), which contributes to IFN responses. TNF- 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- and PGE2 activate STAT-mediated components of human DC maturation by alternative pathways to the IFN-β-mediated autocrine loop used by TLRs.
Key Words: inflammation • Jak
