Role of STK in mouse liver macrophage and endothelial cell responsiveness during acute endotoxemia
ABSTRACT 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: MSP (Macrophage Stimulating Protein; also known as Hepatocyte Growth Factor-like protein (HGFL) and MST1) is a secreted protein and the ligand for transmembrane receptor tyrosine kinase Recepteur d'Origine Nantais (RON; also known as MST1R). Since its discovery, MSP has been demonstrated to play a key role in regulating inflammation in the peripheral tissues of multiple disease models. Recent evidences also point toward a beneficial role of MSP in the regulation of hepatic lipid and glucose metabolism, thereby implicating MSP as a crucial regulator in maintaining metabolic homeostasis while simultaneously suppressing inflammatory processes. In this review, we discuss the recent advances that demonstrate the significance of MSP in metabolic syndrome and build a strong case supporting its therapeutic potential. Copyright © 2014 Elsevier Ltd. All rights reserved.Cytokine & Growth Factor Reviews 10/2014; 26(1). DOI:10.1016/j.cytogfr.2014.10.007 · 6.54 Impact Factor
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ABSTRACT: Endothelin-1 (ET-1) is unique among a broad range of hyperalgesic agents in that it induces hyperalgesia in rats that is markedly enhanced by repeated mechanical stimulation at the site of administration. Antagonists to the ET-1 receptors, ET(A) and ET(B), attenuated both initial as well as stimulation-induced enhancement of hyperalgesia (SIEH) by endothelin. However, administering antisense oligodeoxynucleotide to attenuate ET(A) receptor expression on nociceptors attenuated ET-1 hyperalgesia but had no effect on SIEH, suggesting that this is mediated via a non-neuronal cell. Because vascular endothelial cells are both stretch sensitive and express ET(A) and ET(B) receptors, we tested the hypothesis that SIEH is dependent on endothelial cells by impairing vascular endothelial function with octoxynol-9 administration; this procedure eliminated SIEH without attenuating ET-1 hyperalgesia. A role for protein kinase Cε (PKCε), a second messenger implicated in the induction and maintenance of chronic pain, was explored. Intrathecal antisense for PKCε did not inhibit either ET-1 hyperalgesia or SIEH, suggesting no role for neuronal PKCε; however, administration of a PKCε inhibitor at the site of testing selectively attenuated SIEH. Compatible with endothelial cells releasing ATP in response to mechanical stimulation, P2X(2/3) receptor antagonists eliminated SIEH. The endothelium also appears to contribute to hyperalgesia in two ergonomic pain models (eccentric exercise and hindlimb vibration) and in a model of endometriosis. We propose that SIEH is produced by an effect of ET-1 on vascular endothelial cells, sensitizing its release of ATP in response to mechanical stimulation; ATP in turn acts at the nociceptor P2X(2/3) receptor.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2013; 33(7):2849-59. DOI:10.1523/JNEUROSCI.3229-12.2013 · 6.75 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 · 2.22 Impact Factor