Toll样受体4((toll like receptor4,TLR4)是内毒素(LPS)的关键受体,为Toll蛋白家族中的一个成员,是联系固有免疫和适应性免疫的纽带。TLR4主要表达于髓源性细胞,其启动的胞内信号转导在肝损伤的发生和发展过程中发挥重要作用。这一信号转导途径主要通过NF-κB、p38、JNK等的激活,使细胞产生炎症转录因子,介导肝脏炎症。TLR4与氧化应激的相互作用,使得肝脏对TLR4的配体及细胞因子的敏感性增加,从而加重肝脏损伤。随着TLR4在肝损伤中的作用进一步阐明,其在肝脏疾病中的治疗作用将会产生广阔的应用前景。 相似文献
Toll-like receptors sense invading pathogens by recognizing a wide variety of conserved pathogen-associated molecular patterns(PAMPs).The members of the TLR family selectively utilize adaptor proteins MyD88,TRIF,TIRAP and TRAM to activate overlapping but distinct signal transduction pathways which trigger production of different panels of mediators such as proinflammatory cytokines and type I interferon.These mediators not only control innate immunity but also direct subsequently developed adaptive immunity... 相似文献
The complex biology of Gram-negative bacterial lipopolysaccharide (LPS) is central to the acute inflammatory response in sepsis and related diseases. Repeated treatment with LPS can lead to desensitization or enhancement of subsequent responses both in vitro and in vivo (a phenomenon known as preconditioning). Previous computational studies have demonstrated a role for anti-inflammatory influences in this process (J. Day, J. Rubin, Y. Vodovotz, C.C. Chow, A. Reynolds, G. Clermont, A reduced mathematical model of the acute inflammatory response: II. Capturing scenarios of repeated endotoxin administration. J. Theor. Biol. 242 (2006) 237). Since LPS signals via Toll-like receptor 4 (TLR4), we created a simple mathematical model in order to address the role of this receptor in both the normal and preconditioned response to LPS. We created a non-linear system of ordinary differential equations, consisting of free LPS, free TLR4, bound complex LPS-TLR4, and an intracellular signaling cascade (lumped into a single variable). We simulate the effects of preconditioning by small and large repeated doses of LPS on the system, varying the timing of the doses as well as the rate of expression of TLR4. Our simulations suggest that a simplified model of LPS/TLR4 signaling can account for complex preconditioning phenomena without invoking a specific signaling inhibition mechanism, but rather based on the dynamics of the signaling response itself, as well as the timing and magnitude of the LPS stimuli. 相似文献
Activation of extracellular-regulated kinases 1/2 (ERK) is involved in lipopolysaccharide (LPS)-induced cellular responses such as the increased production of proinflammatory cytokines. However, mitogen-activated protein kinases (MAPKs) such as p38 are also activated by LPS and have been postulated to be important in the control of these end points. Therefore, establishing the relative contribution of MAPKs in each cell type is important, as is elucidating the molecular mechanisms by which these MAPKs are activated in LPS-induced signaling cascades. We demonstrated in DC2.4 dendritic cells that ERK regulates tyrosine phosphorylation of phosphatidyl-inositol-3-kinase (PI3-K) and the production of TNF-alpha. We also demonstrated that Raf1 is phosphorylated and involved in the production of TNF-alpha and tyrosine phosphorylation of PI3-K via ERK. Raf1 also regulates the activation of NF-kappaB. We propose that Raf1 plays a pivotal role in LPS-induced activation of the dendritic cells. 相似文献
Accumulating evidence indicates that activated microglia contribute to the neuropathology involved in many neurodegenerative diseases and after traumatic injury to the CNS. The cytokine transforming growth factor‐beta 1 (TGF‐β1), a potent deactivator of microglia, should have the potential to reduce microglial‐mediated neurodegeneration. It is therefore perplexing that high levels of TGF‐β1 are found in conditions where microglia are chronically activated. We hypothesized that TGF‐β1 signaling is suppressed in activated microglia. We therefore activated primary rat microglia with lipopolysaccharide (LPS) and determined the expression of proteins important to TGF‐β1 signaling. We found that LPS treatment decreased the expression of the TGF‐β receptors, TβR1 and TβR2, and reduced protein levels of Smad2, a key mediator of TGF‐β signaling. LPS treatment also antagonized the ability of TGF‐β to suppress expression of pro‐inflammatory cytokines and to induce microglial cell death. LPS treatment similarly inhibited the ability of the TGF‐β related cytokine, Activin‐A, to down‐regulate expression of pro‐inflammatory cytokines and to induce microglial cell death. Together, these data suggest that microglial activators may oppose the actions of TGF‐β1, ensuring continued microglial activation and survival that eventually may contribute to the neurodegeneration prevalent in chronic neuroinflammatory conditions.
