Disease relevance of Tlr4

• These results suggest involvement of TLR4 in both brain inflammation and neural tissue injury and support the hypothesis that local diffusion and vascular transmission of inflammatory molecules are two major routes for developing inflammation in the brain [1].
• Chlamydophila pneumoniae induces expression of toll-like receptor 4 and release of TNF-alpha and MIP-2 via an NF-kappaB pathway in rat type II pneumocytes [2].
• Regulation of Toll-like receptor 4 expression in the lung following hemorrhagic shock and lipopolysaccharide [3].
• The present study was designed to investigate the role of TLR4 activation by LPS in protecting cardiomyocytes (CM) against apoptosis in an in vitro model of ischemia and to explore the downstream mechanisms leading to the protective effect [4].
• Toll-like receptor 4 detected in exocrine pancreas and the change of expression in cerulein-induced pancreatitis [5].

High impact information on Tlr4

• Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-beta-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment [6].
• Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages [6].
• Consistent with a role for oxidative stress in this effect, in vitro H2O2 treatment of RAW 264.7 macrophages similarly caused an increase in surface TLR4 [6].
• These studies show that alveolar macrophages recovered from rodents subjected to hemorrhagic shock/resuscitation expressed increased surface levels of Toll-like receptor 4 (TLR4), an effect inhibited by adding the antioxidant N-acetylcysteine to the resuscitation fluid [6].
• The H2O2-induced increase in surface TLR4 was prevented by depleting intracellular calcium or disrupting the cytoskeleton, suggesting the involvement of receptor exocytosis [6].

Biological context of Tlr4

• An increase in TLR4 immunoreactivity, coincident with cell death, leukocyte infiltration and neural tissue damage, was found in the meninges, choroid plexus and ventricular ependyma [1].
• We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration [7].
• Taken together, these data suggest an important role of TLR4 signaling via IRAK-1 in protecting against SD-induced apoptosis [4].
• This effect appeared to be due to a lowering of TLR4 mRNA stability by approximately 69% [3].
• Real-time RT-PCR results revealed low-level TLR4 mRNA expression in the rat pancreas, and the change of TLR4 in CIP only developed within the first 4 hours, which is a rapid up-regulation process that peaks at the first hour [5].

Anatomical context of Tlr4

• With LPS treatment, extracellular signals are transduced into macrophages via Toll-like receptor 4 and induce inflammatory mediator production by activating signaling pathways, including the nuclear factor-kappaB (NF-kappaB) pathway and the mitogen-activated protein kinase (MAPK) pathway [8].
• Pericytes express toll-like receptor-4, and is upregulated in response to lipopolysaccharide (LPS) [9].
• Expression of toll-like receptor 4 and MD-2 gene and protein in Kupffer cells after ischemia-reperfusion in rat liver graft [10].
• TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia [7].
• Intratracheal LPS alone induced a rapid reduction in whole lung TLR4 mRNA, an effect which is also observed in recovered alveolar macrophages [3].

Associations of Tlr4 with chemical compounds

• I.c.v. LPS induced the widespread increase in CD14 mRNA but did not change levels of TLR4 transcription in the brain [1].
• Oxidant stress related to shock/resuscitation appeared to contribute to the regulation of TLR4 mRNA, because supplementation of the resuscitation fluid with the antioxidant N-acetylcysteine reversed the ability of shock/resuscitation to preserve TLR4 mRNA levels following LPS [3].
• Angiotensin II upregulates toll-like receptor 4 on mesangial cells [11].
• Cytokine responses to fungal pathogens in Kupffer Cells are Toll-like receptor 4 independent and mediated by tyrosine kinases [12].
• Hydrogen peroxide increased nuclear factor kappaB (NF-kappaB) activation in Chinese hamster ovary fibroblasts that overexpress TLR2 but not in normal or TLR4-overexpressing Chinese hamster ovary cells, an effect that was abrogated by an alpha-TLR2 antibody [13].

Regulatory relationships of Tlr4

• Anti TLR4 antibody can inhibit the production of TNF-alpha induced by LPS [10].

Other interactions of Tlr4

• In the kidney, interleukin-6 messenger RNA was increased, whereas Toll-like receptor 4 messenger RNA was significantly decreased [14].

Analytical, diagnostic and therapeutic context of Tlr4

• By contrast, while shock/resuscitation alone had no effect on TLR4 mRNA levels, it markedly altered the response to LPS [3].
• Considered in aggregate, these data suggest that levels of tlr4 expression are controlled both transcriptionally as well as posttranscriptionally through altered mRNA stability and that antecedent shock/resuscitation, a form of global ischemia/reperfusion, might influence regulation of this gene [3].
• Immunohistochemistry (IHC) was used to detect and localize TLR4 in rat pancreas, and real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to quantitatively determine the expression of TLR4 mRNA in CIP [5].
• Immunostaining and immunoblotting were performed to detect the presence of CD-14, TLR-2, and TLR-4 [15].
• Real-time polymerase chain reaction was used to analyze the presence and quantity of mRNA for CD-14, TLR-2, and TLR-4 [15].

References