Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-alpha and PGE2.
Maturation of dendritic cells (DCs) by TLR ligands induces expression of IFN-beta 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-alpha and PGE2, which induced maturation of human DCs comparably with LPS but did not induce detectable IFN-beta production or Stat1 tyrosine phosphorylation. Consistent with these results, TNF-alpha and PGE2 did not induce Stat1 DNA binding to a standard Stat1-binding oligonucleotide. Instead, TNF-alpha and PGE2 increased Stat1 serine phosphorylation and Stat4 tyrosine phosphorylation and activated expression of the NF-kappaB and Stat1 target gene IFN regulatory factor 1 (IRF1), which contributes to IFN responses. TNF-alpha 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-alpha and PGE2 activate STAT-mediated components of human DC maturation by alternative pathways to the IFN-beta-mediated autocrine loop used by TLRs.
Hu
Yang
Y
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA.
Park-Min
Kyung-Hyun
KH
Yarilina
Anna
A
Ivashkiv
Lionel B
LB
D015703:Antigens, CD / Q000276:immunology; D001483:Base Sequence; D018929:Cell Culture Techniques; D017931:DNA Primers; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D050856:Interferon Regulatory Factor-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016899:Interferon-beta / Q000494:pharmacology; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D017931:DNA Primers; D006684:HLA-DR Antigens; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D009841:Oligonucleotides; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D015232:Dinoprostone