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Infection and Immunity, September 2003, p. 4873-4882, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4873-4882.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance during Salmonella enterica Serovar Typhimurium Infection

Mucosal Immunology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129

Received 14 February 2003/ Returned for modification 23 April 2003/ Accepted 6 June 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-) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-B signaling pathways was relatively unaffected, as was increased expression of TNF- mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-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-. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF- transcript and at least some genes associated with macrophage tolerance.

Editor: A. D. O'Brien

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