17β-Estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage

Hsieh, Ya Ching; Frink, Michael; Thobe, Bjoern M.; Hsu, Jung-Lung; Choudhry, Mashkoor A.; Schwacha, Martin G.; Bland, Kirby I.; Chaudry, Irshad H.

doi:10.1016/j.molimm.2006.11.019

Cited by 55 publications

(40 citation statements)

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“…Furthermore, the decreased Kupffer cell ATP and mtCOI levels were not observed in TLR4 mutant mice following trauma-hemorrhage, suggesting that downregulation of TLR4-dependent ATP production is critical to E2-mediated immunoprotection in Kupffer cells following trauma-hemorrhage (108). Activation of TLR4 initiates an inflammatory cascade involving activation of p38 MAPK, phosphatidylinositol 3-kinase (PI3K), and NF-κB, leading to the release of proinflammatory cytokines (109)(110)(111). Administration of E2 following traumahemorrhage in wild-type mice decreased Kupffer cell TLR4 expression, as well as prevented the phosphorylation of p38 MAPK and NF-κB, suggesting that the protective effect of estradiol on Kupffer cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-κB signaling following traumahemorrhage-which prevents the systemic release of cytokines (109,110).…”

Section: Kupffer Cellsmentioning

confidence: 99%

“…Activation of TLR4 initiates an inflammatory cascade involving activation of p38 MAPK, phosphatidylinositol 3-kinase (PI3K), and NF-κB, leading to the release of proinflammatory cytokines (109)(110)(111). Administration of E2 following traumahemorrhage in wild-type mice decreased Kupffer cell TLR4 expression, as well as prevented the phosphorylation of p38 MAPK and NF-κB, suggesting that the protective effect of estradiol on Kupffer cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-κB signaling following traumahemorrhage-which prevents the systemic release of cytokines (109,110). Upon activation of TLR, MyD88, an adaptor protein that is shared by all TLR pathways, is recruited to TLR receptor domains and links TLR with the downstream intracellular signaling cascades (112,113).…”

Section: Kupffer Cellsmentioning

confidence: 99%

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Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Raju

Bland

Chaudry

2008

Mol Med

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ESTROGEN, MECHANISM OF ACTIONE2, the female hormone, is mainly produced by the ovaries and the placenta. The three major estrogens in women are estradiol, estriol, and estrone ( Figure 1). Estrogens are synthesized from androgens by the loss of C-19 angular methyl group and the formation of an aromatic A ring. Whereas estradiol is derived from testosterone, estrone is derived from androstenedione. The main form of E2 in women Trauma-hemorrhage leads to prolonged immune suppression, sepsis, and multiple organ failure. The condition affects all compartments of the immune system, and extensive studies have been carried out elucidating the immunological events following trauma-hemorrhage. The immune alteration observed following trauma-hemorrhage is gender dependent in both animal models and humans, though some studies in humans are contradictory. Within 30 min after trauma-hemorrhage, splenic and peritoneal macrophages, as well as T-cell function, are depressed in male animals, but not in proestrus females. Studies have also shown that the survival rate and the induction of subsequent sepsis following trauma-hemorrhage are significantly higher in males and ovariectomized females compared with proestrus females. These and other investigations show that sex hormones form the basis of this gender dichotomy, and administration of estrogen can ameliorate the immune depression and increase the survival rate after trauma-hemorrhage. This review specifically elaborates the studies carried out thus far demonstrating immunological alteration after trauma-hemorrhage and its modulation by estrogen. Also, estrogen was shown to produce its salutary effects through nuclear as well as extranuclear receptors. Estrogen rapidly activates several protein kinases and phosphatases, as well as the release of calcium in different cell types. The results of the studies exemplify the promise of estrogen as a therapeutic adjunct in treating adverse pathophysiological conditions following trauma-hemorrhage.

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Section: Kupffer Cellsmentioning

confidence: 99%

Section: Kupffer Cellsmentioning

confidence: 99%

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Raju

Bland

Chaudry

2008

Mol Med

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“…Such molecules, including fibronectin (80), heat shock proteins (81), and high-mobility group box 1 protein (82), may activate TLR4 to cause to the activation of the host immune system and the release of proinflammatory cytokines. Such activation of TLR4 in response to endogenous molecules during stress may explain the observation that the severity of various noninfectious models of critical illness are dependent on the activation of TLR4, including hemorrhagic shock (83)(84)(85)(86) and ischemia reperfusion injury (87)(88). The relative contribution of endogenous vs exogenous molecules in the activation of TLR4 in the pathogenesis of NEC remains of great scientific interest with respect to unraveling the complex origins of NEC.…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair

Leaphart

Cavallo

Gribar

et al. 2007

The Journal of Immunology

426

507

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Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in preterm infants and is characterized by translocation of LPS across the inflamed intestine. We hypothesized that the LPS receptor (TLR4) plays a critical role in NEC development, and we sought to determine the mechanisms involved. We now demonstrate that NEC in mice and humans is associated with increased expression of TLR4 in the intestinal mucosa and that physiological stressors associated with NEC development, namely, exposure to LPS and hypoxia, sensitize the murine intestinal epithelium to LPS through up-regulation of TLR4. In support of a critical role for TLR4 in NEC development, TLR4-mutant C3H/HeJ mice were protected from the development of NEC compared with wild-type C3H/HeOUJ littermates. TLR4 activation in vitro led to increased enterocyte apoptosis and reduced enterocyte migration and proliferation, suggesting a role for TLR4 in intestinal repair. In support of this possibility, increased NEC severity in C3H/HeOUJ mice resulted from increased enterocyte apoptosis and reduced enterocyte restitution and proliferation after mucosal injury compared with mutant mice. TLR4 signaling also led to increased serine phosphorylation of intestinal focal adhesion kinase (FAK). Remarkably, TLR4 coimmunoprecipitated with FAK, and small interfering RNA-mediated FAK inhibition restored enterocyte migration after TLR4 activation, demonstrating that the FAK-TLR4 association regulates intestinal healing. These findings demonstrate a critical role for TLR4 in the development of NEC through effects on enterocyte injury and repair, identify a novel TLR4-FAK association in regulating enterocyte migration, and suggest TLR4/FAK as a therapeutic target in this disease.

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“…Studies have shown the involvement of Toll-like receptors (TLR) 4 and mitogen activated protein kinases (MAPK) in inflammatory response of cells such as Kupffer cells (Thobe, et al 2006; Frink et al 2007; Hsieh et al 2007). However, whether TLR4 and/or MAPK play(s) a role in keratinocytes following trauma-hemorrhage remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

17β-Estradiol normalizes Toll receptor 4, mitogen activated protein kinases and inflammatory response in epidermal keratinocytes following trauma-hemorrhage

Moeinpour

Choudhry

Kawasaki

et al. 2007

Molecular Immunology

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Trauma-hemorrhage produces immunodepression in males but not in proestrus females and this difference is due to the presence of high estrogen in proestrus females. Although skin is the largest immunological organ of the body and is considered the first line of defense, no study to-date has examined whether trauma-hemorrhage has any effects on keratinocytes which are the major epidermal cell type (>90%) of skin. We therefore examined whether epidermal keratinocytes inflammatory response and the signal transduction pathways involved in the inflammatory response are altered following trauma-hemorrhage. C3H/HeN mice were subjected to trauma-hemorrhage and 2 hrs thereafter; keratinocytes were harvested and stimulated with LPS for 24 hrs (5μg/ml). Inflammatory mediators, Toll like receptor (TLR) and myeloid differentiation adaptor protein (MyD88) expression, and the activation of mitogen-activated protein kinase (MAPK) were determined. Trauma-hemorrhage increased the production of IL-6, IL-10, IL-12 and TNF-α, enhanced the expression of TLR4, MyD88 as well as the activation of MAPK proteins (p38, ERK and JNK) in epidermal keratinocytes. However, administration of a single dose of 17β-estradiol following trauma-hemorrhage prevented the increase in these inflammatory parameters under those conditions. These findings suggest that 17β-estradiol normalizes epidermal keratinocytes inflammatory responses following trauma-hemorrhage by preventing the upregulation of TLR4-mediated MAPK activation.

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17β-Estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage

Cited by 55 publications

References 50 publications

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair

17β-Estradiol normalizes Toll receptor 4, mitogen activated protein kinases and inflammatory response in epidermal keratinocytes following trauma-hemorrhage

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