Toll-like receptors (TLRs)1 play a critical role in inducing innate immune responses in mammals by recognizing conserved pathogen-associated molecular patterns of bacteria (1-4). So far, 10 human TLRs have been cloned (5-10). The TLR agonists include lipopolysaccharide (LPS) for TLR4, peptidoglycan for TLR2 and TLR6, double-stranded RNA for TLR3, flagellin for TLR5, and imidazoquinolines and unmethylated CpG motifs in bacterial DNA for TLR7 and TLR9, respectively (3,(11)(12)(13)(14). TLR4 can be activated by nonbacterial agonists such as HSP60, fibronectin, Taxol, respiratory syncytical virus coat protein, and saturated fatty acids (15)(16)(17)(18)(19)(20).TLRs are type I transmembrane receptors characterized by the presence of extracellular leucine-rich repeat motifs and a cytoplasmic Toll/interleukin-1 receptor (TIR) homology domain, which is required for the activation of downstream signaling pathways leading to the activation of nuclear factor-B (NFB) (21). Myeloid differentiation factor-88 (MyD88) is known as an immediate downstream adaptor molecule that interacts directly with the TIR domain of TLRs (22,23). MyD88 recruits interleukin-1 receptor-associated kinase (IRAK) and tumor necrosis factor receptor-associated factor-6 (TRAF6), leading to activation of NFB and mitogenactivated protein kinases (MAPKs) (24,25). Activation of NFB leads to the expression of target genes, including cyclooxygenase-2 (COX-2) and cytokines. TIR domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) is another adaptor molecule cooperating with MyD88, leading to activation of . TIR domaincontaining adaptor inducing interferon- (TRIF)/TIR domain-containing adaptor molecule-1 (TICAM-1) has been reported as another adaptor molecule responsible for the MyD88-independent signaling pathway derived from TLR3, leading to the activation of interferon regulatory factor-3 and the expression of interferon- (29 -31). Thus, individual TLR agonist can activate different downstream signaling pathways,
Toll-like receptor 4 (TLR4) and TLR2 agonists from bacterial origin require acylated saturated fatty acids in their molecules. Previously, we reported that TLR4 activation is reciprocally modulated by saturated and polyunsaturated fatty acids in macrophages. However, it is not known whether fatty acids can modulate the activation of TLR2 or other TLRs for which respective ligands do not require acylated fatty acids. A saturated fatty acid, lauric acid, induced NFB activation when TLR2 was co-transfected with TLR1 or TLR6 in 293T cells, but not when TLR1, 2, 3, 5, 6, or 9 was transfected individually. An n-3 polyunsaturated fatty acid (docosahexaenoic acid (DHA)) suppressed NFB activation and cyclooxygenase-2 expression induced by the agonist for TLR2, 3, 4, 5, or 9 in a macrophage cell line (RAW264.7). Because dimerization is considered one of the potential mechanisms for the activation of TLR2 and TLR4, we determined whether the fatty acids modulate the dimerization. However, neither lauric acid nor DHA affected the heterodimerization of TLR2 with TLR6 as well as the homodimerization of TLR4 as determined by co-immunoprecipitation assays in 293T cells in which these TLRs were transiently overexpressed. Together, these results demonstrate that lauric acid activates TLR2 dimers as well as TLR4 for which respective bacterial agonists require acylated fatty acids, whereas DHA inhibits the activation of all TLRs tested. Thus, responsiveness of different cell types and tissues to saturated fatty acids would depend on the expression of TLR4 or TLR2 with either TLR1 or TLR6. These results also suggest that inflammatory responses induced by the activation of TLRs can be differentially modulated by types of dietary fatty acids. Toll-like receptors (TLRs)1 play a critical role in inducing innate immune responses by recognizing invading microbial pathogens (1-4). The activation of TLRs by agonists recruits an adaptor molecule, MyD88, and initiates the activation of downstream signaling cascades leading to the activation of NFB and mitogen-activated protein kinase and the expression of inflammatory gene products, including cyclooxygenase-2 (COX-2), cytokines, and chemokines (2). Currently, eleven TLRs in mammalian cells are identified, and each TLR responds to different types of agonists: viral double-stranded RNA for TLR3, flagellin and single-stranded RNA for TLR5 and TLR7, respectively, and unmethylated CpG DNA for TLR9 (3)(4)(5)(53)(54)(55). TLR4 recognizes lipopolysaccharide (LPS) derived from Gram-negative bacteria (6 -8). TLR4 can be also activated by non-bacterial agonists such as heat shock protein 60, fibronectin, taxol, respiratory syncytial virus coat protein, and saturated fatty acids (9 -13). TLR2 detects a variety of microbial components such as bacterial lipopeptides, peptidoglycan, and lipoteichoic acids (4). TLR2 forms a heterodimer with TLR1 or TLR6 to respond to and discriminate different types of agonists (4, 14). The activation of diacylated mycoplasmal lipopeptides, macrophage-activating lipopeptide 2...
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