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Irshad H Chaudry - One of the best experts on this subject based on the ideXlab platform.
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mechanism of the salutary effects of estrogen on Kupffer Cell phagocytic capacity following trauma hemorrhage pivotal role of akt activation
Journal of Immunology, 2009Co-Authors: Chi Hsun Hsieh, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Eike A Nickel, Jianguo Chen, Irshad H ChaudryAbstract:Kupffer Cells are macrophages in the liver whose major role is to clear circulating pathogens. Decreased phagocytic capacity of Kupffer Cells may result in severe systemic infection. We tested the hypothesis that the depressed Kupffer Cell phagocytic capacity following trauma-hemorrhage is enhanced by estrogen administration and this occurs due to maintenance of Fc receptor expression and Cellular ATP content via the activation of Akt. Male C3H/HeN mice were subjected to sham operation or trauma-hemorrhage and sacrificed 2 h thereafter. Estrogen, with or without an estrogen receptor antagonist (ICI 182,780), a PI3K inhibitor (Wortmannin), or vehicle, was injected during resuscitation. Kupffer Cell phagocytic capacity was tested in vivo. The expression of Fc receptors, of Akt phosphorylation, of p38 MAPK phosphorylation, of DNA binding activity of NF-κB and ATP content of Kupffer Cells were also determined. Trauma-hemorrhage suppressed Kupffer Cell phagocytosis by decreasing Fc receptor expression and Akt activation; however, it induced p38 MAPK activation and increased NF-κB activity. Cellular ATP levels were also decreased following trauma-hemorrhage. Administration of estrogen following trauma-hemorrhage increased phospho-Akt levels and normalized all the parameters described as well as plasma levels of TNF-α, IL-6, and IL-10. Coadministration of ICI 182,780 or Wortmannin abolished the beneficial effects of estrogen in improving the phagocytic capacity of Kupffer Cells following trauma-hemorrhage. Thus, activation of Akt plays a crucial role in mediating the salutary effect of estrogen in restoring trauma-hemorrhage-induced suppression of Kupffer Cell phagocytosis.
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tlr4 regulates Kupffer Cell chemokine production systemic inflammation and lung neutrophil infiltration following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Michael Frink, Ya Ching Hsieh, Bjoern M Thobe, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Toll-like receptors (TLR) recognize not only microbial products, but also danger signals released from damaged tissues. Although we have previously shown that TLR4 is upregulated following trauma hemorrhage, the exact role of TLR4 in the posttraumatic immune response is unclear. To study this, C3H/HeOuJ (functional TLR4) or C3H/HeJ (TLR4 mutant) mice were subjected to laparotomy and hemorrhagic shock followed by resuscitation with 4x the shed blood volume in the form of Ringer's lactate. Sham operated mice underwent same surgical procedure, but neither hemorrhage nor resuscitation was performed. Four hours after resuscitation, the mice were sacrificed, plasma and lungs were collected and Kupffer Cells were isolated. Plasma chemokine (MCP-1 and KC) levels, Kupffer Cell chemokine production, and lung chemokine content were determined. Lung neutrophil infiltration was assessed by tissue content of myeloperoxidase. The chemokine levels in plasma, Kupffer Cell supernatants and lung tissue were elevated in C3H/HeOuJ mice subjected to trauma hemorrhage compared to shams. No such changes were observed in C3H/HeJ mice undergoing trauma hemorrhage. Mice with functional TLR4 expression showed elevated lung neutrophil infiltration following trauma hemorrhage, which was not observed in TLR4 mutant mice. These findings suggest that functional TLR4 signaling is critical in mediating the inflammatory response following trauma hemorrhage. Thus, modulation of the TLR4 after injury may serve as a future therapeutic target in trauma patients.
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17β estradiol downregulates Kupffer Cell tlr4 dependent p38 mapk pathway and normalizes inflammatory cytokine production following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Ya Ching Hsieh, Michael Frink, Bjoern M Thobe, Junte Hsu, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Although studies have shown that 17β-estradiol (estradiol) normalized Kupffer Cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer Cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-κB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35±5 mmHg ~90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer Cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-κB. This was accompanied by normalization of Kupffer Cell production capacities of IL-6, TNF-α, macrophage inflammatory protein (MIP)-1α, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer Cell p38 MAPK and NF-κB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer Cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-κB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.
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the role of mapk in Kupffer Cell toll like receptor tlr 2 tlr4 and tlr9 mediated signaling following trauma hemorrhage
Journal of Cellular Physiology, 2007Co-Authors: Bjoern M Thobe, Michael Frink, Mashkoor A Choudhry, Martin G Schwacha, Frank Hildebrand, William J Hubbard, Irshad H ChaudryAbstract:Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer Cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP ∼35 mm Hg for 90 min), and resuscitation. Kupffer Cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, Cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-α, MCP-1, and KC production by Kupffer Cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-α and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-α and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer Cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage. J. Cell. Physiol. 210: 667–675, 2007. © 2006 Wiley-Liss, Inc.
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the role of Kupffer Cell α2 adrenoceptors in norepinephrine induced tnf α production
Biochimica et Biophysica Acta, 2001Co-Authors: Mian Zhou, Irshad H Chaudry, Shaolong Yang, Douglas J Koo, David A Ornan, P WangAbstract:Abstract Although previous studies have demonstrated that plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) increase during early sepsis, the precise mechanism responsible for its upregulation remains to be elucidated. Since recent studies have shown that the gut is an important source of norepinephrine (NE) release during early sepsis and enterectomy prior to the onset of sepsis attenuates TNF-α production, we hypothesized that gut-derived NE plays a major role in upregulating TNF-α via the activation of α2-adrenoceptors on Kupffer Cells. To confirm that NE increases TNF-α synthesis and release, Kupffer Cells were isolated from normal rats and incubated with NE (20 or 50 nM) or another α2-adrenergic agonist clonidine (50 nM) without addition of Escherichia coli endotoxin. Supernatant levels of TNF-α were then measured. In additional animals, intraportal infusion of NE (20 μM) with or without the specific α2-adrenergic antagonist yohimbine (1 mM) at a rate of 13 μl/min was carried out for 2 h. Plasma and Kupffer Cell levels of TNF-α were assayed thereafter. Moreover, the effects of NE and yohimbine on TNF-α production was further examined using an isolated perfused liver preparation. The results indicate that both NE and clonidine increased TNF-α release by approximately 4–7-fold in the isolated cultured Kupffer Cells. Similarly, intraportal infusion of NE in vivo or in isolated livers increased TNF-α synthesis and release which was inhibited by co-infusion of yohimbine. Furthermore, the increased Cellular levels of TNF-α in Kupffer Cells after in vivo administration of NE was also blocked by yohimbine. These results, taken together, suggest that gut-derived NE upregulates TNF-α production in Kupffer Cells through an α2-adrenergic pathway, which appears to be responsible at least in part for the increased levels of circulating TNF-α observed during early sepsis as well as other pathophysiologic conditions such as trauma, hemorrhagic shock, or gut ischemia/reperfusion.
Mashkoor A Choudhry - One of the best experts on this subject based on the ideXlab platform.
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mechanism of the salutary effects of estrogen on Kupffer Cell phagocytic capacity following trauma hemorrhage pivotal role of akt activation
Journal of Immunology, 2009Co-Authors: Chi Hsun Hsieh, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Eike A Nickel, Jianguo Chen, Irshad H ChaudryAbstract:Kupffer Cells are macrophages in the liver whose major role is to clear circulating pathogens. Decreased phagocytic capacity of Kupffer Cells may result in severe systemic infection. We tested the hypothesis that the depressed Kupffer Cell phagocytic capacity following trauma-hemorrhage is enhanced by estrogen administration and this occurs due to maintenance of Fc receptor expression and Cellular ATP content via the activation of Akt. Male C3H/HeN mice were subjected to sham operation or trauma-hemorrhage and sacrificed 2 h thereafter. Estrogen, with or without an estrogen receptor antagonist (ICI 182,780), a PI3K inhibitor (Wortmannin), or vehicle, was injected during resuscitation. Kupffer Cell phagocytic capacity was tested in vivo. The expression of Fc receptors, of Akt phosphorylation, of p38 MAPK phosphorylation, of DNA binding activity of NF-κB and ATP content of Kupffer Cells were also determined. Trauma-hemorrhage suppressed Kupffer Cell phagocytosis by decreasing Fc receptor expression and Akt activation; however, it induced p38 MAPK activation and increased NF-κB activity. Cellular ATP levels were also decreased following trauma-hemorrhage. Administration of estrogen following trauma-hemorrhage increased phospho-Akt levels and normalized all the parameters described as well as plasma levels of TNF-α, IL-6, and IL-10. Coadministration of ICI 182,780 or Wortmannin abolished the beneficial effects of estrogen in improving the phagocytic capacity of Kupffer Cells following trauma-hemorrhage. Thus, activation of Akt plays a crucial role in mediating the salutary effect of estrogen in restoring trauma-hemorrhage-induced suppression of Kupffer Cell phagocytosis.
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tlr4 regulates Kupffer Cell chemokine production systemic inflammation and lung neutrophil infiltration following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Michael Frink, Ya Ching Hsieh, Bjoern M Thobe, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Toll-like receptors (TLR) recognize not only microbial products, but also danger signals released from damaged tissues. Although we have previously shown that TLR4 is upregulated following trauma hemorrhage, the exact role of TLR4 in the posttraumatic immune response is unclear. To study this, C3H/HeOuJ (functional TLR4) or C3H/HeJ (TLR4 mutant) mice were subjected to laparotomy and hemorrhagic shock followed by resuscitation with 4x the shed blood volume in the form of Ringer's lactate. Sham operated mice underwent same surgical procedure, but neither hemorrhage nor resuscitation was performed. Four hours after resuscitation, the mice were sacrificed, plasma and lungs were collected and Kupffer Cells were isolated. Plasma chemokine (MCP-1 and KC) levels, Kupffer Cell chemokine production, and lung chemokine content were determined. Lung neutrophil infiltration was assessed by tissue content of myeloperoxidase. The chemokine levels in plasma, Kupffer Cell supernatants and lung tissue were elevated in C3H/HeOuJ mice subjected to trauma hemorrhage compared to shams. No such changes were observed in C3H/HeJ mice undergoing trauma hemorrhage. Mice with functional TLR4 expression showed elevated lung neutrophil infiltration following trauma hemorrhage, which was not observed in TLR4 mutant mice. These findings suggest that functional TLR4 signaling is critical in mediating the inflammatory response following trauma hemorrhage. Thus, modulation of the TLR4 after injury may serve as a future therapeutic target in trauma patients.
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17β estradiol downregulates Kupffer Cell tlr4 dependent p38 mapk pathway and normalizes inflammatory cytokine production following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Ya Ching Hsieh, Michael Frink, Bjoern M Thobe, Junte Hsu, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Although studies have shown that 17β-estradiol (estradiol) normalized Kupffer Cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer Cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-κB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35±5 mmHg ~90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer Cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-κB. This was accompanied by normalization of Kupffer Cell production capacities of IL-6, TNF-α, macrophage inflammatory protein (MIP)-1α, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer Cell p38 MAPK and NF-κB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer Cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-κB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.
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the role of mapk in Kupffer Cell toll like receptor tlr 2 tlr4 and tlr9 mediated signaling following trauma hemorrhage
Journal of Cellular Physiology, 2007Co-Authors: Bjoern M Thobe, Michael Frink, Mashkoor A Choudhry, Martin G Schwacha, Frank Hildebrand, William J Hubbard, Irshad H ChaudryAbstract:Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer Cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP ∼35 mm Hg for 90 min), and resuscitation. Kupffer Cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, Cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-α, MCP-1, and KC production by Kupffer Cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-α and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-α and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer Cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage. J. Cell. Physiol. 210: 667–675, 2007. © 2006 Wiley-Liss, Inc.
Martin G Schwacha - One of the best experts on this subject based on the ideXlab platform.
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mechanism of the salutary effects of estrogen on Kupffer Cell phagocytic capacity following trauma hemorrhage pivotal role of akt activation
Journal of Immunology, 2009Co-Authors: Chi Hsun Hsieh, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Eike A Nickel, Jianguo Chen, Irshad H ChaudryAbstract:Kupffer Cells are macrophages in the liver whose major role is to clear circulating pathogens. Decreased phagocytic capacity of Kupffer Cells may result in severe systemic infection. We tested the hypothesis that the depressed Kupffer Cell phagocytic capacity following trauma-hemorrhage is enhanced by estrogen administration and this occurs due to maintenance of Fc receptor expression and Cellular ATP content via the activation of Akt. Male C3H/HeN mice were subjected to sham operation or trauma-hemorrhage and sacrificed 2 h thereafter. Estrogen, with or without an estrogen receptor antagonist (ICI 182,780), a PI3K inhibitor (Wortmannin), or vehicle, was injected during resuscitation. Kupffer Cell phagocytic capacity was tested in vivo. The expression of Fc receptors, of Akt phosphorylation, of p38 MAPK phosphorylation, of DNA binding activity of NF-κB and ATP content of Kupffer Cells were also determined. Trauma-hemorrhage suppressed Kupffer Cell phagocytosis by decreasing Fc receptor expression and Akt activation; however, it induced p38 MAPK activation and increased NF-κB activity. Cellular ATP levels were also decreased following trauma-hemorrhage. Administration of estrogen following trauma-hemorrhage increased phospho-Akt levels and normalized all the parameters described as well as plasma levels of TNF-α, IL-6, and IL-10. Coadministration of ICI 182,780 or Wortmannin abolished the beneficial effects of estrogen in improving the phagocytic capacity of Kupffer Cells following trauma-hemorrhage. Thus, activation of Akt plays a crucial role in mediating the salutary effect of estrogen in restoring trauma-hemorrhage-induced suppression of Kupffer Cell phagocytosis.
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tlr4 regulates Kupffer Cell chemokine production systemic inflammation and lung neutrophil infiltration following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Michael Frink, Ya Ching Hsieh, Bjoern M Thobe, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Toll-like receptors (TLR) recognize not only microbial products, but also danger signals released from damaged tissues. Although we have previously shown that TLR4 is upregulated following trauma hemorrhage, the exact role of TLR4 in the posttraumatic immune response is unclear. To study this, C3H/HeOuJ (functional TLR4) or C3H/HeJ (TLR4 mutant) mice were subjected to laparotomy and hemorrhagic shock followed by resuscitation with 4x the shed blood volume in the form of Ringer's lactate. Sham operated mice underwent same surgical procedure, but neither hemorrhage nor resuscitation was performed. Four hours after resuscitation, the mice were sacrificed, plasma and lungs were collected and Kupffer Cells were isolated. Plasma chemokine (MCP-1 and KC) levels, Kupffer Cell chemokine production, and lung chemokine content were determined. Lung neutrophil infiltration was assessed by tissue content of myeloperoxidase. The chemokine levels in plasma, Kupffer Cell supernatants and lung tissue were elevated in C3H/HeOuJ mice subjected to trauma hemorrhage compared to shams. No such changes were observed in C3H/HeJ mice undergoing trauma hemorrhage. Mice with functional TLR4 expression showed elevated lung neutrophil infiltration following trauma hemorrhage, which was not observed in TLR4 mutant mice. These findings suggest that functional TLR4 signaling is critical in mediating the inflammatory response following trauma hemorrhage. Thus, modulation of the TLR4 after injury may serve as a future therapeutic target in trauma patients.
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17β estradiol downregulates Kupffer Cell tlr4 dependent p38 mapk pathway and normalizes inflammatory cytokine production following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Ya Ching Hsieh, Michael Frink, Bjoern M Thobe, Junte Hsu, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Although studies have shown that 17β-estradiol (estradiol) normalized Kupffer Cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer Cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-κB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35±5 mmHg ~90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer Cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-κB. This was accompanied by normalization of Kupffer Cell production capacities of IL-6, TNF-α, macrophage inflammatory protein (MIP)-1α, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer Cell p38 MAPK and NF-κB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer Cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-κB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.
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the role of mapk in Kupffer Cell toll like receptor tlr 2 tlr4 and tlr9 mediated signaling following trauma hemorrhage
Journal of Cellular Physiology, 2007Co-Authors: Bjoern M Thobe, Michael Frink, Mashkoor A Choudhry, Martin G Schwacha, Frank Hildebrand, William J Hubbard, Irshad H ChaudryAbstract:Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer Cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP ∼35 mm Hg for 90 min), and resuscitation. Kupffer Cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, Cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-α, MCP-1, and KC production by Kupffer Cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-α and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-α and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer Cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage. J. Cell. Physiol. 210: 667–675, 2007. © 2006 Wiley-Liss, Inc.
Michael Frink - One of the best experts on this subject based on the ideXlab platform.
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tlr4 regulates Kupffer Cell chemokine production systemic inflammation and lung neutrophil infiltration following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Michael Frink, Ya Ching Hsieh, Bjoern M Thobe, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Toll-like receptors (TLR) recognize not only microbial products, but also danger signals released from damaged tissues. Although we have previously shown that TLR4 is upregulated following trauma hemorrhage, the exact role of TLR4 in the posttraumatic immune response is unclear. To study this, C3H/HeOuJ (functional TLR4) or C3H/HeJ (TLR4 mutant) mice were subjected to laparotomy and hemorrhagic shock followed by resuscitation with 4x the shed blood volume in the form of Ringer's lactate. Sham operated mice underwent same surgical procedure, but neither hemorrhage nor resuscitation was performed. Four hours after resuscitation, the mice were sacrificed, plasma and lungs were collected and Kupffer Cells were isolated. Plasma chemokine (MCP-1 and KC) levels, Kupffer Cell chemokine production, and lung chemokine content were determined. Lung neutrophil infiltration was assessed by tissue content of myeloperoxidase. The chemokine levels in plasma, Kupffer Cell supernatants and lung tissue were elevated in C3H/HeOuJ mice subjected to trauma hemorrhage compared to shams. No such changes were observed in C3H/HeJ mice undergoing trauma hemorrhage. Mice with functional TLR4 expression showed elevated lung neutrophil infiltration following trauma hemorrhage, which was not observed in TLR4 mutant mice. These findings suggest that functional TLR4 signaling is critical in mediating the inflammatory response following trauma hemorrhage. Thus, modulation of the TLR4 after injury may serve as a future therapeutic target in trauma patients.
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17β estradiol downregulates Kupffer Cell tlr4 dependent p38 mapk pathway and normalizes inflammatory cytokine production following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Ya Ching Hsieh, Michael Frink, Bjoern M Thobe, Junte Hsu, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Although studies have shown that 17β-estradiol (estradiol) normalized Kupffer Cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer Cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-κB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35±5 mmHg ~90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer Cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-κB. This was accompanied by normalization of Kupffer Cell production capacities of IL-6, TNF-α, macrophage inflammatory protein (MIP)-1α, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer Cell p38 MAPK and NF-κB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer Cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-κB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.
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the role of mapk in Kupffer Cell toll like receptor tlr 2 tlr4 and tlr9 mediated signaling following trauma hemorrhage
Journal of Cellular Physiology, 2007Co-Authors: Bjoern M Thobe, Michael Frink, Mashkoor A Choudhry, Martin G Schwacha, Frank Hildebrand, William J Hubbard, Irshad H ChaudryAbstract:Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer Cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP ∼35 mm Hg for 90 min), and resuscitation. Kupffer Cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, Cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-α, MCP-1, and KC production by Kupffer Cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-α and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-α and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer Cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage. J. Cell. Physiol. 210: 667–675, 2007. © 2006 Wiley-Liss, Inc.
Bjoern M Thobe - One of the best experts on this subject based on the ideXlab platform.
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tlr4 regulates Kupffer Cell chemokine production systemic inflammation and lung neutrophil infiltration following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Michael Frink, Ya Ching Hsieh, Bjoern M Thobe, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Toll-like receptors (TLR) recognize not only microbial products, but also danger signals released from damaged tissues. Although we have previously shown that TLR4 is upregulated following trauma hemorrhage, the exact role of TLR4 in the posttraumatic immune response is unclear. To study this, C3H/HeOuJ (functional TLR4) or C3H/HeJ (TLR4 mutant) mice were subjected to laparotomy and hemorrhagic shock followed by resuscitation with 4x the shed blood volume in the form of Ringer's lactate. Sham operated mice underwent same surgical procedure, but neither hemorrhage nor resuscitation was performed. Four hours after resuscitation, the mice were sacrificed, plasma and lungs were collected and Kupffer Cells were isolated. Plasma chemokine (MCP-1 and KC) levels, Kupffer Cell chemokine production, and lung chemokine content were determined. Lung neutrophil infiltration was assessed by tissue content of myeloperoxidase. The chemokine levels in plasma, Kupffer Cell supernatants and lung tissue were elevated in C3H/HeOuJ mice subjected to trauma hemorrhage compared to shams. No such changes were observed in C3H/HeJ mice undergoing trauma hemorrhage. Mice with functional TLR4 expression showed elevated lung neutrophil infiltration following trauma hemorrhage, which was not observed in TLR4 mutant mice. These findings suggest that functional TLR4 signaling is critical in mediating the inflammatory response following trauma hemorrhage. Thus, modulation of the TLR4 after injury may serve as a future therapeutic target in trauma patients.
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17β estradiol downregulates Kupffer Cell tlr4 dependent p38 mapk pathway and normalizes inflammatory cytokine production following trauma hemorrhage
Molecular Immunology, 2007Co-Authors: Ya Ching Hsieh, Michael Frink, Bjoern M Thobe, Junte Hsu, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H ChaudryAbstract:Although studies have shown that 17β-estradiol (estradiol) normalized Kupffer Cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer Cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-κB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35±5 mmHg ~90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer Cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-κB. This was accompanied by normalization of Kupffer Cell production capacities of IL-6, TNF-α, macrophage inflammatory protein (MIP)-1α, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer Cell p38 MAPK and NF-κB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer Cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-κB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.
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the role of mapk in Kupffer Cell toll like receptor tlr 2 tlr4 and tlr9 mediated signaling following trauma hemorrhage
Journal of Cellular Physiology, 2007Co-Authors: Bjoern M Thobe, Michael Frink, Mashkoor A Choudhry, Martin G Schwacha, Frank Hildebrand, William J Hubbard, Irshad H ChaudryAbstract:Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer Cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP ∼35 mm Hg for 90 min), and resuscitation. Kupffer Cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, Cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-α, MCP-1, and KC production by Kupffer Cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-α and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-α and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer Cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage. J. Cell. Physiol. 210: 667–675, 2007. © 2006 Wiley-Liss, Inc.
