Role of STK in mouse liver macrophage and endothelial cell responsiveness during acute endotoxemia
Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, 160 Frelinghuysen Rd., Piscataway, NJ 08854, USA.Journal of leukocyte biology (Impact Factor: 4.29). 05/2010; 88(2):373-82. DOI: 10.1189/jlb.0210113
Acute endotoxemia is associated with excessive production of proinflammatory mediators by hepatic macrophages and endothelial cells, which have been implicated in liver injury and sepsis. In these studies, we analyzed the role of MSP and its receptor STK in regulating the activity of these cells. Acute endotoxemia, induced by administration of LPS (3 mg/kg) to mice, resulted in increased expression of STK mRNA and protein in liver macrophages and endothelial cells, an effect that was dependent on TLR-4. This was correlated with decreased MSP and increased pro-MSP in serum. In Kupffer cells, but not endothelial cells, MSP suppressed LPS-induced NOS-2 expression, with no effect on COX-2. LPS treatment of mice caused a rapid (within 3 h) increase in the proinflammatory proteins NOS-2, IL-1beta, and TNF-alpha, as well as TREM-1 and TREM-3 and the anti-inflammatory cytokine IL-10 in liver macrophages and endothelial cells. Whereas LPS-induced expression of proinflammatory proteins was unchanged in STK-/- mice, IL-10 expression was reduced significantly. Enzymes mediating eicosanoid biosynthesis including COX-2 and mPGES-1 also increased in macrophages and endothelial cells after LPS administration. In STK-/- mice treated with LPS, mPGES-1 expression increased, although COX-2 expression was reduced. LPS-induced up-regulation of SOD was also reduced in STK-/- mice in liver macrophages and endothelial cells. These data suggest that MSP/STK signaling plays a role in up-regulating macrophage and endothelial cell anti-inflammatory activity during hepatic inflammatory responses. This may be important in protecting the liver from tissue injury.
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ABSTRACT: The past several years have seen the accumulation of evidence demonstrating that tissue injury induced by diverse toxicants is due not only to their direct effects on target tissues but also indirectly to the actions of resident and infiltrating macrophages. These cells release an array of mediators with cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activity, which function to fight infections, limit tissue injury, and promote wound healing. However, following exposure to toxicants, macrophages can become hyperresponsive, resulting in uncontrolled or dysregulated release of mediators that exacerbate acute tissue injury and/or promote the development of chronic diseases such as fibrosis and cancer. Evidence suggests that the diverse activity of macrophages is mediated by distinct subpopulations that develop in response to signals within their microenvironment. Understanding the precise roles of these different macrophage populations in the pathogenic response to toxicants is key to designing effective treatments for minimizing tissue damage and chronic disease and for facilitating wound repair.Annual Review of Pharmacology 11/2010; 51(1):267-88. DOI:10.1146/annurev.pharmtox.010909.105812 · 18.37 Impact Factor
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ABSTRACT: This study was undertaken to clarify the effects of taurine on liver injury in rats with severe acute pancreatitis (SAP). Rats were randomly assigned to three groups: a sham operation (SO), a SAP (established by infusion of 5% taurocholate), and a SAP given taurine (Taur). At 12 and 24 h post-operation, taurine pretreatment significantly attenuated hepatic tissue injury induced by SAP, and concurrently, serum alanine aminotransferase, aspartate transaminase, and amylase levels were significantly reduced by taurine pretreatment. Compared with the SO group, the total and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) expression and nuclear factor-κB (NF-κB) activity of Kupffer cells (KCs) were significantly higher in the SAP group, but taurine pretreatment inhibited the total and phosphorylated p38 MAPK expression and NF-κB activity of KCs in the SAP group. The increase of tumor necrosis factor-α and interleukin-lβ in cultured supernate of the SAP rat-derived KCs was also significantly inhibited by taurine pretreatment. These results suggest that taurine pretreatment ameliorated liver injury in rats with SAP mainly by inhibiting phosphorylated p38 MAPK and NF-κB activity in KCs, which may play an important role in liver injury.Inflammation 08/2011; 35(2):690-701. DOI:10.1007/s10753-011-9362-0 · 2.21 Impact Factor
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ABSTRACT: Aim: Glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) plays pro-inflammatory roles in immune response. Thus, our aim was to assess if dexamethasone attenuates lipopolysaccharide (LPS)-induced liver injury by affecting GITRL in Kupffer cells (KC). Methods: A BALB/c mouse model of liver injury was established by i.p. injecting with LPS (10 mg/kg) co-treated with or without dexamethasone (3 mg/kg). Blood and liver samples were obtained for analysis of liver morphology, GITRL expression, hepatocellular function and cytokine levels at 24 h after injection. KC were isolated and challenged by LPS (1 µg/mL), with or without dexamethasone (10 µM) co-treatment, or with GITRL siRNA pre-transfection. The GITRL expression and cytokine levels were assayed at 24 h after challenge. Results: Dexamethasone treatment significantly improved the survival rate of endotoxemic mice (P < 0.05), whereas serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and γ-interferon levels were significantly decreased (P < 0.05, respectively). Concurrently, LPS-induced hepatic tissue injury was attenuated as indicated by morphological analysis; and expression of GITRL in liver tissue and KC was downregulated (P < 0.05). Consistent with these in vivo experiments, inhibited expression of GITRL, TNF-α and IL-6 caused by dexamethasone treatment were also observed in LPS-stimulated KC. The GITRL, TNF-α and IL-6 expression was also significantly inhibited by GITRL gene silencing. Conclusion: The TNF-α and IL-6 expression of LPS-stimulated KC was inhibited by GITRL gene silencing. Dexamethasone attenuates LPS-induced liver injury, at least proportionately, by downregulating GITRL in KC.Hepatology Research 10/2011; 41(10):989-99. DOI:10.1111/j.1872-034X.2011.00852.x · 2.74 Impact Factor
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