Toshchakov Vladimir, Jones Bryan W, Perera Pin-Yu, Thomas Karen, Cody M Joshua, Zhang Shuling, Williams Bryan R G, Major Jennifer, Hamilton Thomas A, Fenton Matthew J, Vogel Stefanie N
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Nat Immunol. 2002 Apr;3(4):392-8. doi: 10.1038/ni774. Epub 2002 Mar 18.
Toll-like receptor 2 (TLR2) agonists induce a subset of TLR4-inducible proinflammatory genes, which suggests the use of differential signaling pathways. Murine macrophages stimulated with the TLR4 agonist Escherichia coli lipopolysaccharide (LPS), but not with TLR2 agonists, induced phosphorylation of signal transducer and activator of transcription 1alpha (STAT1alpha) and STAT1beta, which was blocked by antibodies to interferon beta (IFN-beta) but not IFN-alpha. All TLR2 agonists poorly induced IFN-beta, which is encoded by an immediate early LPS-inducible gene. Thus, the failure of TLR2 agonists to induce STAT1-dependent genes resulted, in part, from their inability to express IFN-beta. TLR4-induced IFN-beta mRNA was MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein)-dependent. Together, these findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.
Toll样受体2（TLR2）激动剂可诱导一部分TLR4诱导的促炎基因，这表明存在不同的信号通路。用TLR4激动剂大肠杆菌脂多糖（LPS）刺激的小鼠巨噬细胞可诱导信号转导和转录激活因子1α（STAT1α）和STAT1β的磷酸化，而用TLR2激动剂刺激则不会，这种磷酸化被抗干扰素β（IFN-β）抗体阻断，但不被IFN-α抗体阻断。所有TLR2激动剂诱导IFN-β的能力都很差，IFN-β由一个立即早期LPS诱导基因编码。因此，TLR2激动剂无法诱导依赖STAT1的基因，部分原因是它们无法表达IFN-β。TLR4诱导的IFN-β mRNA不依赖MyD88和PKR（双链RNA依赖性蛋白激酶），但依赖TIRAP（含Toll样白细胞介素1受体结构域的衔接蛋白）。这些发现共同为TLR4和TLR2激动剂激活的基因表达差异模式提供了首个机制基础。
