title: TGF-beta down-regulates IL-1alpha-induced TLR2 expression in murine hepatocytes.
abstract: We have previously reported that the proinflammatory cytokine interleukin (IL)-1alpha can up-regulate functional Toll-like receptor 2 (TLR2) expression in primary-cultured murine hepatocytes, and bacterial lipopeptide (BLP) is capable of signaling through TLR2 to induce serum amyloid A (SAA) expression in hepatocytes. In the present study, we investigated the effect of the anti-inflammatory cytokine transforming growth factor-beta (TGF-beta) on TLR2 expression in primary-cultured murine hepatocytes. At the mRNA and protein levels, TGF-beta up-regulated TLR2 expression but inhibited TLR2 expression induced by IL-1alpha at 24 h. BLP-induced SAA promoter activity could be augmented by pretreatment with IL-1alpha but not TGF-beta or the combination of TGF-beta and IL-1alpha. TLR2 promoter activity and nuclear factor (NF)-kappaB activation by IL-1alpha were inhibited by TGF-beta treatment. Pretreatment with TGF-beta strongly suppressed IL-1alpha-induced TLR2 promoter activity and NF-kappaB activation, which was consistent with the down-regulation of type I IL-1 receptor (IL-1RI) mRNA expression. IL-1alpha up-regulated IL-1RI mRNA, but it was inhibited by the treatment with TGF-beta. These results suggest that TGF-beta suppresses the induction of TLR2 expression by IL-1alpha through down-regulation of IL-1RI expression. These results also demonstrate the disparity between IL-1alpha and TGF-beta in regulating TLR2-mediated SAA production in hepatocytes.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumura
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Takemasa
authors.initials: T
authors.lastname: Takii
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Thorn
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Whitehead
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Inoue
authors.forename: Kikuo
authors.initials: K
authors.lastname: Onozaki
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000235:genetics; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D001053:Apolipoproteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D000685:Serum Amyloid A Protein; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta