Bosisio Daniela, Polentarutti Nadia, Sironi Marina, Bernasconi Sergio, Miyake Kensuke, Webb Ginette R, Martin Michael U, Mantovani Alberto, Muzio Marta
Department of Immunology and Cell Biology, Mario Negri Institute, Milano, Italy.
Blood. 2002 May 1;99(9):3427-31. doi: 10.1182/blood.v99.9.3427.
In human monocytes and macrophages, interferon-gamma (IFNgamma) augmented mRNA and surface expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Expression of the accessory component MD-2 and of the adapter protein MyD88 was also increased. LPS increased TLR4 mRNA levels, but concomitantly decreased its surface expression. IFNgamma counteracted the LPS-induced downregulation of TLR4. IFNgamma-primed monocytes showed increased responsiveness to LPS in terms of phosphorylation of the interleukin-1 receptor-associated kinase (IRAK; immediately downstream of the MyD88 adapter protein), NF-kB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor alpha [TNFalpha] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNgamma of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.
在人类单核细胞和巨噬细胞中，γ干扰素（IFNγ）可增强Toll样受体4（TLR4）的mRNA及表面表达，TLR4是细菌脂多糖（LPS）信号受体复合物的关键组成部分。辅助成分MD-2及衔接蛋白髓样分化因子88（MyD88）的表达也会增加。LPS可提高TLR4的mRNA水平，但同时会降低其表面表达。IFNγ可抵消LPS诱导的TLR4下调。经IFNγ预处理的单核细胞在白细胞介素-1受体相关激酶（IRAK；位于MyD88衔接蛋白下游）磷酸化、核因子κB（NF-κB）DNA结合活性以及相应的细胞因子（肿瘤坏死因子α [TNFα]和白细胞介素-12 [IL-12]）产生方面，对LPS的反应性增强。这些结果表明，TLR4表达增强是IFNγ长期以来使单核吞噬细胞对病原体识别和杀伤致敏以及其与LPS在巨噬细胞激活中协同作用的基础。
