Li Qian, Cherayil Bobby J
Mucosal Immunology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Infect Immun. 2003 Sep;71(9):4873-82. doi: 10.1128/IAI.71.9.4873-4882.2003.
Toll-like receptors (TLRs) play an important role in the innate immune response, particularly in the initial interaction between the infecting microorganism and phagocytic cells, such as macrophages. We investigated the role of TLR4 during infection of primary murine peritoneal macrophages with Salmonella enterica serovar Typhimurium. We found that macrophages from the C3H/HeJ mouse strain, which carries a functionally inactive Tlr4 gene, exhibit marked impairment of tumor necrosis factor alpha (TNF-alpha) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-kappa B signaling pathways was relatively unaffected, as was increased expression of TNF-alpha mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-kappa B p50 and p52 subunits, was induced by S. enterica serovar Typhimurium even in the absence of functional TLR4. These results indicate that during infection of macrophages by S. enterica serovar Typhimurium, TLR4 signals are required at a posttranscriptional step to maximize secretion of TNF-alpha. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF-alpha transcript and at least some genes associated with macrophage tolerance.
Toll样受体（TLRs）在天然免疫反应中发挥重要作用，尤其是在感染性微生物与吞噬细胞（如巨噬细胞）之间的初始相互作用中。我们研究了TLR4在鼠伤寒沙门氏菌感染原代小鼠腹腔巨噬细胞过程中的作用。我们发现，携带功能失活Tlr4基因的C3H/HeJ小鼠品系的巨噬细胞，在对鼠伤寒沙门氏菌感染的反应中，肿瘤坏死因子α（TNF-α）分泌明显受损。然而，细胞外生长因子调节激酶和NF-κB信号通路的激活相对未受影响，TNF-α mRNA的表达增加也是如此。此外，即使在没有功能性TLR4的情况下，鼠伤寒沙门氏菌也能诱导巨噬细胞耐受性，这与NF-κB p50和p52亚基表达增加有关。这些结果表明，在鼠伤寒沙门氏菌感染巨噬细胞的过程中，TLR4信号在转录后步骤是最大化TNF-α分泌所必需的。TLR4以外的模式识别受体传递的信号足以增加TNF-α转录本以及至少一些与巨噬细胞耐受性相关基因的表达。
