Disease relevance of Tlr2

• Toll-like receptor 2 and mitogen- and stress-activated kinase 1 are effectors of Mycobacterium avium-induced cyclooxygenase-2 expression in macrophages [1].
• We recently demonstrated that a new PG1828-encoded lipoprotein (PG1828LP) was able to be separated from a Porphyromonas gingivalis lipopolysaccharide (LPS) preparation, and we found that it exhibited strong cell activation, similar to that of Escherichia coli LPS, through a Toll-like receptor 2 (TLR2)-dependent pathway [2].
• Recognition of Gram-positive bacteria by Toll-like receptor 2 (TLR2) induces activation of proinflammatory pathways [3].
• Toll-like receptor 2 (TLR2) mediates astrocyte activation in response to the Gram-positive bacterium Staphylococcus aureus [4].
• Lipopolysaccharide preparation extracted from Porphyromonas gingivalis lipoprotein-deficient mutant shows a marked decrease in toll-like receptor 2-mediated signaling [2].
• Behavioral studies using toll-like receptor 2 knock-out mice demonstrate that the expression of toll-like receptor 2 is required for the induction of mechanical allodynia and thermal hyperalgesia due to spinal nerve axotomy [5].

High impact information on Tlr2

• Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria [6].
• Moreover, NOD2 deficiency or the presence of a Crohn disease-like Card15 mutation increased Toll-like receptor 2-mediated activation of NF-kappa B-c-Rel, and T(H)1 responses were enhanced [7].
• All TLR2 agonists poorly induced IFN-beta, which is encoded by an immediate early LPS-inducible gene [8].
• Together, these findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists [8].
• Murine macrophages stimulated with the TLR4 agonist Escherichia coli lipopolysaccharide (LPS), but not with TLR2 agonists, induced phosphorylation of signal transducer and activator of transcription 1alpha (STAT1alpha) and STAT1beta, which was blocked by antibodies to interferon beta (IFN-beta) but not IFN-alpha [8].

Chemical compound and disease context of Tlr2

• Our study demonstrates, by using a trinitrobenzene sulfonic acid-induced colitis model of Crohn's disease, the constitutive expression and the up-regulation of TLR2 and -4 at messenger and protein levels in colon extracts, as well as in macrophages, dendritic cells, and lymphocytes from mesenteric lymphoid nodes [9].
• flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2) [10].
• Consequently, the ability of medroxyprogesterone acetate to suppress lipopolysaccharide-induced up-regulation of Toll-like receptor 2 messenger RNA may be one of the mechanisms by which progestins are able to decrease preterm birth [11].
• Here, we provide evidence that exposure of the murine macrophage cell line J774 to the TLR2 ligands; 19-kDa or zymosan, but not the TLR4 ligand LPS, inhibits IFN-gamma-induced killing of Mycobacterium bovis Bacillus Calmette-Guérin (BCG) [12].
• Tripalmitoyl-S-glyceryl-cysteine-dependent OspA vaccination of toll-like receptor 2-deficient mice results in effective protection from Borrelia burgdorferi challenge [13].

Biological context of Tlr2

• We now show that triggering of mouse peritoneal neutrophils with Toll-like receptor 2 (TLR2), TLR4, and TLR9 ligands, but not ligands of TLR3, induces upregulation of surface membrane TNF-alpha [14].
• The results demonstrate that TLR2 is essential for maximal proinflammatory cytokine and chemokine production, but not phagocytosis, in primary astrocytes following S. aureus and PGN exposure [4].
• Analysis of the gene expression profiles in adipocytes showed that high fat intake induced the expression of toll-like receptor 2 (TLR2) in addition to TNFalpha [15].
• High fat intake induces a population of adipocytes to co-express TLR2 and TNFalpha in mice with insulin resistance [15].
• MyD88-dependent but Toll-like receptor 2-independent innate immunity to Listeria: no role for either in macrophage listericidal activity [16].

Anatomical context of Tlr2

• In these experiments, we found activation of Akt in neutrophils stimulated with the TLR2-specific ligands peptidoglycan and the lipopeptide tri-palmitoyl-S-glyceryl-Cys-Ser-(Lys)(4) that occurred earlier and was of greater magnitude than that present after exposure to the TLR4 agonist LPS [17].
• Neutrophils are critical initiators and effectors of the innate immune system and express Toll-like receptor 2 (TLR2) and TLR4 [17].
• However, the functional significance of TLR2 in mediating astrocyte activation remains unknown [4].
• A tumor necrosis factor alpha enzyme-linked immunosorbent assay further confirmed that P. gingivalis LPS and FimA activate mouse peritoneal macrophages via TLR2 [18].
• Free fatty acids increased TNFalpha expression in 3T3-L1 adipocytes through TLR2 signals [15].

Associations of Tlr2 with chemical compounds

• The greater sensitivity of MDP-stimulated cells to LPS may explain the data that were once interpreted incorrectly as indicating that Tlr2 is the endotoxin receptor [19].
• Phosphoinositide 3-kinase and Akt occupy central roles in inflammatory responses of Toll-like receptor 2-stimulated neutrophils [17].
• Intravascular choline-containing cell walls bound to endothelial cells and caused rapid lethality in wild-type, Tlr2(-/-), and Nod2(-/-) mice but not in Pafr(-/-) mice [20].
• The major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), is recognized by Toll-like receptor 2 (TLR2), TLR4, and CD14 [21].
• With ceftriaxone therapy, none of the wt but 27% of the TLR2(-/-) mice died (P<.04) [22].

Physical interactions of Tlr2

• Furthermore, the increase in restriction enzyme accessibility at the TLR2 promoter region did not appear to result from binding of NF-kappa B, but rather depended on a TLR2-myeloid differentiation factor 88 signaling pathway [23].

Regulatory relationships of Tlr2

• Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells [24].
• These results suggest that TGF-beta suppresses the induction of TLR2 expression by IL-1alpha through down-regulation of IL-1RI expression [25].
• Amyloid beta peptide 1-40 enhances the action of Toll-like receptor-2 and -4 agonists but antagonizes Toll-like receptor-9-induced inflammation in primary mouse microglial cell cultures [26].
• These data suggest that mycobacteria inhibit IFN-gamma-induced gene expression by multiple pathways involving both TLR2 and non-TLR receptors [27].
• Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma [28].

Other interactions of Tlr2

• In contrast, Tlr4, Tlr2, and Cd14 KO mice showed no deficits in the production of IL-6 [29].
• IFN-gamma, a cytokine sensitizing to endotoxin, was induced by P. acnes in splenocytes of TLR2-/- and TLR9-/- but not MyD88-/- mice [3].
• The level of IFNGR-1 mRNA also decreased in TLR2-stimulated RAW264.7 cells and M. avium-infected cells [30].
• Mphi from interleukin (IL)-1 receptor type I-/-, Toll-like receptor 2 (TLR2-/-) and RAGE-/- mice were used to investigate the role of these receptors in HMGB1 signalling [31].
• Interestingly, the activation of TLR2 by live P. gingivalis inhibited the release of RANTES, VCAM-1, and IL-1alpha from mouse peritoneal macrophages [18].

Analytical, diagnostic and therapeutic context of Tlr2

• In addition, both stimuli led to a significant increase in TLR2 mRNA expression in wild-type astrocytes as assessed by real-time quantitative RT-PCR [4].
• Neither CD14 nor Toll-like receptor 4 gene-deficient mice responded to intranasal administration of LPS, whereas Toll-like receptor 2 knockout mice were indistinguishable from wild-type animals [32].
• A subsequent analysis of TLR2 and TLR4 gene expression by quantitative PCR indicated that TLR4 function induces TLR2 expression and vice versa [33].
• Microarray analysis confirmed that TLR2 plays a central role in PGN recognition by primary microglia [34].
• Protection against hepatic ischemia/reperfusion injury via downregulation of toll-like receptor 2 expression by inhibition of Kupffer cell function [35].

References