title: LPS regulates SOCS2 transcription in a type I interferon dependent autocrine-paracrine loop.
abstract: Recent studies suggest that SOCS2 is involved in the regulation of TLR signaling. In this study, we found that the expression of SOCS2 is regulated in human monocyte-derived DC by ligands stimulating TLR2, 3, 4, 5, 8 and 9 signaling. SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. Blocking endogenous type I IFN signaling, by neutralizing antibodies to the receptor IFNAR2, abolished SOCS2 mRNA expression after TLR4 stimulation. Transcription factors STAT3, 5 and 6 displayed putative binding sites in the promoter regions of the human SOCS2 gene. Subsequent silencing experiments further supported that STAT3 and STAT5 are involved in LPS induced SOCS2 regulation. In mice we show that SOCS2 mRNA induction is 45% lower in bone marrow derived macrophages derived from MyD88(-/-) mice, and do not increase in BMMs from IRF3(-/-) mice after BCG infection. In conclusion, our results suggest that TLR4 signaling indirectly increases SOCS2 in late phase mainly via the production of endogenous type I IFN, and that subsequent IFN receptor signaling activates SOCS2 via STAT3 and STAT5.
authors.affiliation: Translational Immunology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jin
authors.initials: J
authors.lastname: Hu
authors.forename: DaoHua
authors.initials: D
authors.lastname: Lou
authors.forename: Berit
authors.initials: B
authors.lastname: Carow
authors.forename: Malin E
authors.initials: ME
authors.lastname: Winerdal
authors.forename: Martin
authors.initials: M
authors.lastname: Rottenberg
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Wikström
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norstedt
authors.forename: Ola
authors.initials: O
authors.lastname: Winqvist
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D019899:Paracrine Communication / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C106643:SOCS2 protein, human; D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins