Matsumura Takayuki, Hayashi Hidetoshi, Takii Takemasa, Thorn Caroline F, Whitehead Alexander S, Inoue Jun-Ichiro, Onozaki Kikuo
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
J Leukoc Biol. 2004 Jun;75(6):1056-61. doi: 10.1189/jlb.0104108. Epub 2004 Mar 23.
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.
我们之前报道过，促炎细胞因子白细胞介素（IL）-1α可上调原代培养的小鼠肝细胞中功能性Toll样受体2（TLR2）的表达，并且细菌脂肽（BLP）能够通过TLR2发出信号，诱导肝细胞中血清淀粉样蛋白A（SAA）的表达。在本研究中，我们调查了抗炎细胞因子转化生长因子-β（TGF-β）对原代培养的小鼠肝细胞中TLR2表达的影响。在mRNA和蛋白质水平上，TGF-β上调了TLR2的表达，但在24小时时抑制了IL-1α诱导的TLR2表达。用IL-1α预处理可增强BLP诱导的SAA启动子活性，但TGF-β或TGF-β与IL-1α的组合则不能。TGF-β处理可抑制IL-1α诱导的TLR2启动子活性和核因子（NF）-κB激活。用TGF-β预处理可强烈抑制IL-1α诱导的TLR2启动子活性和NF-κB激活，这与I型IL-1受体（IL-1RI）mRNA表达的下调一致。IL-1α上调了IL-1RI mRNA，但TGF-β处理可抑制这种上调。这些结果表明，TGF-β通过下调IL-1RI表达来抑制IL-1α对TLR2表达的诱导。这些结果还证明了IL-1α和TGF-β在调节肝细胞中TLR2介导的SAA产生方面的差异。
