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.

Vascular Endothelial Cells Mediate Mechanical Stimulation-Induced Enhancement of Endothelin Hyperalgesia via Activation of P2X2/3Receptors on Nociceptors

“…Of note in this regard, PKCε can affect activity in the mitochondrial electron transport chain (Nowak et al, 2004; Costa and Garlid, 2008); and it has been shown, in other cells, that PKCε can translocate to mitochondria (Joseph and Levine, 2006; Ferrari and Levine, 2010) where it can phosphorylate proteins including members of the mitochondrial electron transport chain complex (Costa and Garlid, 2008). Since endothelial cells can be activated by mechanical stimuli such as shear stress (Binti Md Isa et al, 2011; Hennig et al, 2011) signaling via the mitochondrial electron transport chain in endothelial cells (Ali et al, 2004; Zhang et al, 2005) can lead to the release of a number of pronociceptive mediators (e.g., prostaglandins, ATP, nitric oxide, endothelin-1, platelet-derived growth factor, interleukin-1, interleukin-6 and ROS (Corl et al, 2008; Iwata et al, 2010; Laskin et al, 2010), and mechanical stimulation of the endothelial cell releases ATP (Milner et al, 1990), the endothelial cell is a compelling candidate for mediating SIEH.…”

Taurine Attenuates Liver Injury by Downregulating Phosphorylated p38 MAPK of Kupffer Cells in Rats with Severe Acute Pancreatitis

“…All animals were housed under specific pathogen-free conditions and allowed free access to sterile water and food. These animals received humane care in compliance with the institution's guidelines, as outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences [17]. All experimental protocols described in this study complied with the Chongqing Medical University Ethics Review Committee for Animal Experimentation.…”

Macrophages and Tissue Injury: Agents of Defense or Destruction?

“…Following hepatotoxicant exposure, expression of the M2 macrophage chemokine MCP-1 [monocyte chemotactic protein-1, also known as chemokine (C-C motif) ligand 2] and its receptor CCR2 [chemokine (C-C motif) receptor 2] is upregulated in the liver, as is expression of the M2-inducing cytokines IL-4, IL-10, and IL-13 (3, 6, 37, 43–46). This correlates with increased numbers of macrophages expressing M2 markers including arginase, STK/RON (stem cell–derived tyrosine kinase/recepteur d’origine nantais), Ym1, and/or Fizz1 at sites of injury (47, 48). Production of anti-inflammatory and mitogenic proteins, such as TGFβ and VEGF, is also increased (3, 36–38, 44–47, 49–52).…”