title: Altered endothelin-1 signaling in production of thromboxane A2 in kupffer cells from bile duct ligated rats.
abstract: Kupffer cells (KCs), the liver resident macrophages accounting for 80-90% of the total population of fixed tissue macrophages in the body, not only play a key role in host defense via removing particulate materials from the portal circulation, but may also contribute to the pathogenesis of various liver diseases. We have previously demonstrated that KCs play an important role in controlling portal hypertension and hepatocellular injury via releasing thromboxane A2 (TXA2) in early fibrosis induced by one-week bile duct ligation (BDL). Production of TXA2 is controlled by cytosolic phospholipase A2 (cPLA2) that is activated by the interaction of entothelin-1 (ET-1) with its G-protein coupled ET receptor B (ETBR). However, the signaling pathways that contribute to the ET-1-induced activation of cPLA2 and production of TXA2 in KCs in the normal healthy or injured livers are not yet clear, which are investigated in the present study using isolated KCs from one-week BDL or sham rats. The pharmacological inhibition of cPLA2 or chelation of intracellular calcium abrogated the ET-1 induction of TXA2 from KCs. Compared to those from sham rats, KCs from BDL animals displayed a significantly enhanced responsiveness of p38 MAPK to ET-1, increased ETBR and Galphai subunit but decreased Galphaq and Galpha11 expression. Inhibition of ERK1/2 or Gq signaling abrogated significantly the ET-1 induction of TXA2 in sham KCs but only slightly in BDL KCs. In contrast, inhibition of p38 MAPK and Gi signaling markedly attenuated the ET-1 induction of TXA2 in BDL KCs but had no effect in sham KCs. Lastly, inhibition of PLC or PKC abrogated ET-1 induction of TXA2 in KCs from both sham and BDL groups. The hepatic stress (such as BDL) induces significant modifications in the receptor and intermediates of ET-1 signaling in KC and subsequently alters ET-1 signaling mechanisms, particularly a shift from Gq induced signaling to Gi induced signaling, in the activation of cPLA2 and production of TXA2 in response to ET-1.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Miller
authors.forename: Jian X
authors.initials: JX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism*; D008297:Male; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D013928:Thromboxane A2; D054510:Phospholipases A2, Cytosolic; D019204:GTP-Binding Proteins; D002118:Calcium