Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death.
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PMID:Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. 1769 52

The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor alpha (TNFalpha). Anti-HMGB-1 antibody suppressed TNFalpha upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFalpha and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.
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PMID:Early release of HMGB-1 from neurons after the onset of brain ischemia. 1800 May 11

Heat shock protein (HSP) 72 is released by cells during stress and injury. HSP-72 also stimulates the release of cytokines in macrophages by binding to Toll-like receptors (TLR) 2 and 4. Circulating levels of HSP-72 increase during hepatic ischemia-reperfusion injury. The role of extracellular HSP-72 (eHSP-72) in the injury response to ischemia-reperfusion is unknown. Therefore, the objective of the present study was to determine whether eHSP-72 has any direct effects on hepatocytes. Primary mouse hepatocytes were treated with purified human recombinant HSP-72. Conditioned media were evaluated by ELISA for the cytokines, TNF-alpha, IL-6, and macrophage inflammatory protein 2 (MIP-2). Stimulation of hepatocytes with eHSP-72 did not induce production of TNFalpha or IL-6 but resulted in dose-dependent increases in MIP-2 production. To evaluate the pathway responsible for this response, expression of TLR2 and TLR4 was confirmed on hepatocytes by immunohistochemistry. Hepatocyte production of MIP-2 was significantly decreased in hepatocytes obtained from TLR2 or TLR4 knockout mice. MIP-2 production was found to be partially dependent on NF-kappaB because inhibition of NF-kappaB with Bay 11-7085 significantly decreased eHSP-72-induced MIP-2 production. Inhibitors of p38 mitogen-activated protein kinase or c-Jun NH(2)-terminal kinase had no effect on production of MIP-2 induced by eHSP-72. The data suggest that eHSP-72 binds to TLR2 and TLR4 on hepatocytes and signals through NF-kappaB to increase MIP-2 production. The fact that eHSP-72 did not increase TNF-alpha or IL-6 production may be indicative of a highly regulated signaling pathway downstream from TLR.
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PMID:Activation of hepatocytes by extracellular heat shock protein 72. 1850 12

Ischemia-reperfusion (I/R) injuries are implicated in a large array of pathological conditions such as myocardial infarction, cerebral stroke, and hepatic, renal, and intestinal ischemia, as well as following cardiovascular and transplant surgeries. The hallmark of these pathologies is excessive inflammation. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. Endogenous ligands such as low-molecular hyaluronic acid, fibronectin, heat shock protein 70, and heparin sulfate were all found to be cleaved in the inflamed tissue and to activate TLR2 and TLR4, initiating an inflammatory response even in the absence of pathogens and infiltrating immune cells. In this review, we discuss the contribution of TLR activation in hepatic, renal, cerebral, intestinal, and myocardial I/R injuries. A greater understanding of the role of TLRs in I/R injuries may aid in the development of specific TLR-targeted therapeutics to treat these conditions.
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PMID:Toll-like receptors in ischemia-reperfusion injury. 1900 78

Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.
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PMID:Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart. 1901 Oct 41

Using an in vitro ischemia model (ischemic solution; IS model) that induces penumbral cell death, we examined the effect of 4,4'-diisothio-cyanostilbene-2,2'-disulfonic acid (DIDS) on cell injury/death and underlying molecular mechanisms. Propidium iodide (PI) uptake was used to quantify cell death in organotypic hippocampal slice cultures. A 24-h IS exposure caused a fivefold increase in mean PI fluorescence intensity. DIDS, dose-dependently (1-4000 microM), reduced the IS-induced PI uptake in hippocampal CA1 neurons with an IC(50) of 26 microM. This protective effect of DIDS was reversible and effective even 6 h following the onset of IS treatment. Gene expression profiling studies indicated that among approximately 46,000 transcripts tested, the most significantly up-regulated gene by IS was interleukin-1beta (IL-1beta) which was also the most significantly down-regulated gene when DIDS was added to the IS-treated slices. The addition of a recombinant IL-1 receptor antagonist (100 microg/mL) or neutralizing IL-1beta antibody significantly attenuated the IS-induced cell death, indicating that the up-regulation of IL-1beta with IS treatment contributed to the IS-induced cell death. Toll-like receptor 2 (TLR2), another gene that was significantly up-regulated by IS and suppressed by DIDS, was studied to determine whether it was related to the IL-1beta up-regulation. Indeed, this was the case as the IS-induced IL-1beta up-regulation was abolished in TLR2-/- mouse brain slices. Furthermore, the IS-induced cell death was significantly reduced in TLR2-/- when compared with that in wild-type slices, indicating that TLR2 is functionally upstream of IL-1beta in this IS model. We conclude that (i) IS up-regulates TLR2 expression and augments TLR2 signaling, causing over-expression of IL-1beta which leads to cell death and (ii) DIDS blocks IS-induced neuronal injury, at least partially, by suppressing the TLR2 pathway.
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PMID:DIDS protects against neuronal injury by blocking Toll-like receptor 2 activated-mechanisms. 1907 53

Ischemia/reperfusion injury (IRI) induces an innate immune response, leading to an inflammatory reaction and tissue damage that have been attributed to engagement of the Toll-like receptor (TLR) 2 and 4. However, the respective roles of TLR2 and/or TLR4 in mediating downstream activation of mitogen-activated protein kinase (MAPK) pathways during IRI have not been fully elucidated. Here we show that extracellular signal-regulated kinase (ERK)1/2 is activated in both intact kidneys and cultured renal tubule epithelial cells (RTECs) from wildtype and Tlr4 knockout mice, but not those from Tlr2 knockout mice subjected to transient ischemia. Geldanamycin (GA), an inhibitor of heat shock protein 90 and reticulum endoplasmic-resident gp96, and gp96 mRNA silencing (siRNA), did not affect ERK1/2 activation in either post-hypoxic wild-type or Tlr4-deficient RTECs, but did restore its activation in post-hypoxic Tlr2-deficient RTECs. Immunoprecipitation studies revealed that gp96 co-immunoprecipitates with the serine-threonine protein phosphatase 5 (PP5), identified as a negative modulator of the mitogen extracellular kinase (MEK)-ERK pathway, in unstressed wild-type and post-hypoxic Tlr2-deficient RTECs. In contrast, PP5 co-immunoprecipitation with gp96 was strikingly reduced in post-hypoxic wild-type RTECs, suggesting that the inactivation of PP5 resulting from the dissociation of PP5 from gp96 allows the activation of ERK1/2 to occur. Inhibition of PP5 by okadaic acid, and Pp5 siRNA also restored TLR2-mediated phosphorylation of ERK1/2, and apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK)-mediated apoptosis in post-hypoxic Tlr2-deficient RTECs. These findings indicate that gp96 interacts with PP5 and controls TLR2-mediated induction of ERK1/2 in post-hypoxic renal tubule cells.
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PMID:Heat shock protein gp96 interacts with protein phosphatase 5 and controls toll-like receptor 2 (TLR2)-mediated activation of extracellular signal-regulated kinase (ERK) 1/2 in post-hypoxic kidney cells. 1926 98

Stimulation of TLRs by exogenous and endogenous ligands triggers expression of several genes that are involved in innate immune responses. Recently, a role of TLR4 in the myocardial response to injury separate from microbial pathogens has been examined in experimental studies. TLR4 deficient mice sustain significantly smaller infarctions compared with wild-type control mice given similar areas at risk. Levels of serum cytokines such as IL-1b, IL-6, and TNFa are increased after ischemia/reperfusion, but these responses are attenuated in TLR4 deficient mice compared to control mice. TLR2 signaling also importantly contributes to cardiac dysfunction following ischemia/reperfusion. MyD88, a key adaptor protein for TLR signaling, is responsible for the protective effects of TLR signaling inhibition in ischemia/reperfusion injury. TLR4 gene polymorphism (Asp299Gly) attenuates innate immune responsiveness, reduces the risk for coronary artery disease, and increases a chance of longevity. The innate immune system is clearly involved in the pathogenesis of cardiovascular diseases and could be a new therapeutic target.
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PMID:Role of Toll-like receptor mediated signaling pathway in ischemic heart. 1927 19

Since first being described in the fruit fly Drosophila melanogaster, Toll-like receptors (TLRs) have proven to be of great interest to immunologists and investigators interested in the molecular basis to inflammation. They recognize pathogen-derived factors and also products of inflamed tissue, and trigger signaling pathways that lead to activation of transcription factors such as nuclear factor-kappaB and the interferon regulatory factors. These in turn lead to induction of immune and inflammatory genes, including such important cytokines as tumor necrosis factor-alpha and type I interferon. Much evidence points to a role for TLRs in immune and inflammatory diseases and increasingly in cancer. Examples include clear roles for TLR4 in sepsis, rheumatoid arthritis, ischemia/reperfusion injury, and allergy. TLR2 has been implicated in similar pathologic conditions and also in systemic lupus erythematosus (SLE) and tumor metastasis. TLR7 has also been shown to be important in SLE. TLR5 has been shown to be radioprotective. Recent advances in our understanding of signaling pathways activated by TLRs, structural insights into TLRs bound to their ligands and antagonists, and approaches to inhibit TLRs (including antibodies, peptides, and small molecules) are providing possiblemeans by which to interfere with TLRs clinically. Here we review these recent advances and speculate about whether manipulating TLRs is likely to be successful in fighting off different diseases.
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PMID:Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. 1947 10

Ischemia-reperfusion (IR) triggers tissue injury by activating innate immunity, for example, via TLR2 and TLR4. Surprisingly, TLR signaling in intrinsic renal cells predominates in comparison to intrarenal myeloid cells in the postischemic kidney. We hypothesized that immune cell activation is specifically suppressed in the postischemic kidney, for example, by single Ig IL-1-related receptor (SIGIRR). SIGIRR deficiency aggravated postischemic acute renal failure in association with increased renal CXCL2/MIP2, CCL2/MCP-1, and IL-6 mRNA expression 24 h after IR. Consistent with this finding interstitial neutrophil and macrophage counts were increased and tubular cell necrosis was aggravated in Sigirr-deficient vs wild-type IR kidneys. In vivo microscopy revealed increased leukocyte transmigration in the postischemic microvasculature of Sigirr-deficient mice. IL-6 and CXCL2/MIP2 release was much higher in Sigirr-deficient renal myeloid cells but not in Sigirr-deficient tubular epithelial cells after transient hypoxic culture conditions. Renal IR studies with chimeric mice confirmed this finding, as lack of SIGIRR in myeloid cells largely reproduced the phenotype of renal IR injury seen in Sigirr(-/-) mice. Additionally, clodronate depletion of dendritic cells prevented the aggravated renal failure in Sigirr(-/-) mice. Thus, loss of function mutations in the SIGIRR gene predispose to acute renal failure because SIGIRR prevents overshooting tissue injury by suppressing the postischemic activation of intrarenal myeloid cells.
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PMID:Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein. 1969 46


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