Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling

Abstract

TLR are primary triggers of the innate immune system by recognizing various microorganisms through conserved pathogen-associated molecular patterns. TLR2 is the receptor for a functional recognition of bacterial lipopeptides (LP) and is up-regulated during various disorders such as chronic obstructive pulmonary disease and sepsis. This receptor is unique in its ability to form heteromers with TLR1 or TLR6 to mediate intracellular signaling. According to the fatty acid pattern as well as the assembling of the polypeptide tail, LP can signal through TLR2 in a TLR1- or TLR6-dependent manner. There are also di- and triacylated LP, which stimulate TLR1-deficient cells and TLR6-deficient cells. In this study, we investigated whether heterodimerization evolutionarily developed to broaden the ligand spectrum or to induce different immune responses. We analyzed the signal transduction pathways activated through the different TLR2 dimers using the three LP, palmitic acid (Pam)octanoic acid (Oct)(2)C-(VPGVG)(4)VPGKG, fibroblast-stimulating LP-1, and Pam(2)C-SK(4). Dominant-negative forms of signaling molecules, immunoblotting of MAPK, as well as microarray analysis indicate that all dimers use the same signaling cascade, leading to an identical pattern of gene activation. We conclude that heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of LP present in various pathogens. Thus, although mycoplasma and Gram-positive and Gram-negative bacteria may activate different TLR2 dimers, the development of different signal pathways in response to different LP does not seem to be of vital significance for the innate defense system.

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

“…A similar observation was made using Pam2EQL as a model. Moreover, the engagement of TLR2 led to the activation of multiple signaling pathways in DCs, including JNK, p38, ERK, MyD88, and NF-kB signaling (32,33). Our data showed that the upregulation of Rab7 is dependent on MyD88 pathway (Fig.…”

“…4B, 4C). Previous studies showed TLR2 activation resulted in downstream MAPK signaling, such as JNK, p38, and ERK signaling (32,33). To further investigate the signaling pathways of TLR2 that regulate Rab7 expression, MAPK signaling inhibitors were used to treat BMDCs.…”

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

“…Casp1 is an enzyme involved in the up-regulation of inflammation and apoptosis [25], while Lpar1 is a GPCR involved in developmental, physiologic and pathophysiologic processes, and has also been shown to activate PKB as well as Rho pathways [26]. In addition, Tnfsf14 and Tnfrsf1b both have been shown to play a role in the activation of NFκB and apoptosis [21], while Tlr6, through its interaction with Tlr2, is involved in the immune response [27]. Hence, it appears that PKB inhibition leads to an increase in the abundance of mRNAs arising from genes important for induction of apoptosis, suggesting a role for PKB in the inhibition of apoptosis following nuclear βAR stimulation.…”

Recognition of Corynebacterium pseudodiphtheriticum by Toll-like receptors and up-regulation of antimicrobial peptides in human corneal epithelial cells

“…17 Gram-positive bacteria are known to activate and mediate downstream signaling through heterodimerization of either TLR2/1 or TLR2/6. 18 Since TLR6 is downregulated in ulcers obtained from patients, C. pseudodiphtheriticum might initiate cell signaling via TLR2/1. However, the case is little different in immortalized cell lines, where both TLR1 and TLR6 is up-regulated and thus both TLR2/1 and TLR2/6 might be activated.…”