Differential effects of Gram‐positiveversusGram‐negative bacteria on NOSII and TNFαin macrophages: role of TLRs in synergy between the two

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Abstract
Gram‐negative and Gram‐positive bacteria are sensed by Toll‐like receptor (TLR)4 and TLR2, respectively. TLR4 recruits MyD88 and TRIF, whereas TLR2 recruits MyD88 without TRIF. NOSII and TNFαare central genes in innate immunity and are thought to be differentially regulated by the MyD88versusTRIF signalling pathways. Here, we have used Gram‐positiveStaphylococcus aureus, Gram‐negativeEscherichia coliand highly selective TLR ligands to establish the precise relationship between TLR2, TLR1, TLR6 and TLR4 for NOSIIversusTNFαinduction. In murine macrophages at 24 h,E. colior LPS (TLR4) induced NO and TNFαrelease. In contrast,S. aureus(TLR2/TLR1/TLR6) or Pam3CSK4 (TLR2/TLR1), or FSL‐1 and LTA (TLR2/TLR6) induced TNFαwithout an effect on NO. At later time points (48–72 h),S. aureusinduced NO release. The ability ofS. aureus, but notE. colior LPS, to induce NO release was inhibited by anti‐TNFα‐binding antibodies. At 24 h, LPS synergised with TLR2 ligands to induce NO release and NOSII protein expression. LPS also induced the expression of TLR2 gene expression without affecting levels of TLR4. Using cells from TLR2−/−or TLR4−/−mice, the ability of LPS to synergise withS. aureusor Pam3CSK4 was found to be dependent on both TLR2 and TLR4. These observations are the first to clearly delineate the role of separately activating TLR2 and TLR4 in the induction of NOSII and TNFαgenes compared with their coinduction when both receptor pathways are activated. British Journal of Pharmacology(2006)148, 1067–1075. doi:10.1038/sj.bjp.0706815