Role of Toll-like receptor 4 in macrophage activation and tolerance during Salmonella enterica serovar Typhimurium infection.
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.
Li
Qian
Q
Mucosal Immunology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Cherayil
Bobby J
BJ
D000818:Animals; D007108:Immune Tolerance; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D016328:NF-kappa B / Q000096:biosynthesis; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D008562:Membrane Glycoproteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha