Whereas TLR4 activation induces a speedy acute response, the inflammatory response to TLR2, demonstrated by the induction of IL6 in our case, is slower, but surprisingly prolonged. Hence, even though activation of both recep tors elicits an inflammatory response, TLR2 induces a chronic inflammatory state. Despite the fact that peptidoglycan rec ognition protein and NOD have already been shown to mediate peptidoglycan response in some cell forms, their function in mediating the response obtained within this experiment is restricted for the reason that immunoneutralization having a TLR2 certain antibody entirely ablates response to peptidoglycan, and a TLR2 precise siRNA drastically reduces IL6 induction by peptidoglycan. Obesity and sort 2 diabetes are related having a chronic low grade systemic and adipose tissue inflammation.
Interestingly, obesity and sort 2 diabetes are also associated with increased expression of TLR2, and obesity induces the expression of a subset of adipocytes that more than express both TLR2 and TNF. The reduction in selelck kinase inhibitor the expression of adiponectin receptors in response to TLR2 activation with peptidoglycan also agrees with the locating that these receptors are downregulated in adipose tissue of obese and insulin resistant mice. This raises the pos sibility that activation of TLR2 in obesity could contribute to a state of adiponectin resistance in obesity. Since adi ponectin exerts anti inflammatory effects, a reduc tion in the expression of its receptors could attenuate this essential function of adiponectin. Hence, TLR2 may possibly be a crucial player in the perpetuation of inflammation that characterizes obesity.
Our perform and that of other individuals have shown that several sig naling pathways mediate LPS induction of IL6. These pathways incorporate NFB, c JNK, ERK, inhibitory G protein and PKC mediated processes. Toll like receptors activate related but distinct signaling pathways as a result of their ability to recruit various adapter proteins. TLR2 is capable to recruit TIRAP Mal, and this TWS119 permits it to regulate the expression of a distinct set of inflammatory genes which include IL6, TNFand IL12. Our work has shown that inhibition of NFB failed to suppress induction of IL6 by peptidoglycan and also had no effect on TLR2 mRNA expression. It really is unknown whether this observation is distinctive for the 3T3 L1 adipocytes or associated to our experi mental circumstances, but parallels the inability of NFB inhibition to suppress IL6 induction by LPS in myocytes.
Nonetheless, added research will be required to completely characterize the uniqueness of the signaling characteristics of TLR2 in adipocytes in comparison with other toll recep tors. The strong induction of TLR2 mRNA by both LPS and peptidoglycan that was observed within this study clearly sup ports a part for TLR2 as a strong marker of inflammation in adipocytes. This corroborates the induction of TLR2, but not TLR4, by LPS in mouse splenic macrophages.