{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T19:35:19Z","timestamp":1791056119550,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":3318,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,8]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Compelling experimental evidence indicates that the interactions between endotoxin and hepatic stellate cells (HSCs) can play a significant role in the pathogenesis of liver disease. Endotoxin-induced release of a multifunctional mediator NO (via inducible NO synthase) and the proinflammatory cytokines tumor necrosis factor \u03b1 (TNF-\u03b1) and interleukin (IL)-6 by HSCs could be an important mechanism of pathological changes in the liver. However, the signaling mechanisms of these effects are poorly understood. In this study, we found that endotoxin causes activation of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated protein kinase [ERK] 1 and 2, p38, and c-Jun NH2-terminal kinase [JNK]) and nuclear factor \u03baB (NF-\u03baB) and production of H2O2 in culture-activated HSCs. However, only p38 and NF-\u03baB were found to be responsible for the synthesis of NO, IL-6, and TNF-\u03b1. Exogenous H2O2 caused modest stimulation of TNF-\u03b1 synthesis, did not affect the synthesis of NO or IL-6, and did not activate NF-\u03baB or MAPKs. Inhibition of p38 and NF-\u03baB activation by SB203580 and pyrrolidine dithiocarbamate, respectively, blocked endotoxin-induced H2O2, NO, TNF-\u03b1, and IL-6 synthesis. Inhibition of ERK1\/2 and JNK phosphorylation did not alter these effects of endotoxin. Whereas SB203580 inhibited endotoxin-induced NF-\u03baB activation, pyrrolidine dithiocarbamate did not affect p38 phosphorylation in endotoxin-stimulated cells.<\/jats:bold>\n                                 <jats:bold>\n                                    In conclusion\n                                 <\/jats:bold>\n                                 <jats:bold>, endotoxin-induced synthesis of NO, TNF-\u03b1, and IL-6 in HSCs is mediated by p38 and NF-\u03baB, with involvement of H2O2 in TNF-\u03b1 production.<\/jats:bold>\n                                 <jats:bold>\n                                    Supplementary material for this article can be found on the HEPATOLOGY website\n                                 <\/jats:bold> (http:\/\/interscience.wiley.com\/jpages\/0270-9139\/suppmat\/index.html).<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.21254","type":"journal-article","created":{"date-parts":[[2006,7,26]],"date-time":"2006-07-26T19:19:35Z","timestamp":1153941575000},"page":"389-398","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":93,"title":["Mechanisms of endotoxin-induced NO, IL-6, and TNF-\u03b1 production in activated rat hepatic stellate cells: Role of p38 MAPK"],"prefix":"10.1097","volume":"44","author":[{"given":"Chinnasamy","family":"Thirunavukkarasu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon C.","family":"Watkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrashekhar R.","family":"Gandhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R2-14-20241201","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1055\/s-2007-1007128","article-title":"Biology of hepatic stellate cells and their possible relevance in the pathogenesis of portal hypertension in cirrhosis.","volume":"19","author":"Pinzani","year":"1999","journal-title":"Sem Liver Dis"},{"key":"R3-14-20241201","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1074\/jbc.275.4.2247","article-title":"Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.","volume":"275","author":"Friedman","year":"2000","journal-title":"J Biol Chem"},{"key":"R4-14-20241201","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1055\/s-2001-17554","article-title":"Cytokine receptors and signaling in hepatic stellate cells.","volume":"21","author":"Pinzani","year":"2001","journal-title":"Semin Liver Dis"},{"key":"R5-14-20241201","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1055\/s-2001-17555","article-title":"Interactions between hepatic stellate cells and the immune system.","volume":"21","author":"Maher","year":"2001","journal-title":"Semin Liver Dis"},{"key":"R6-14-20241201","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1136\/gut.19.10.935","article-title":"Portal and systemic bacteraemia and endotoxaemia in liver disease.","volume":"19","author":"Triger","year":"1978","journal-title":"Gut"},{"key":"R7-14-20241201","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/hep.1840080207","article-title":"Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis.","volume":"8","author":"Lumsden","year":"1988","journal-title":"HEPATOLOGY"},{"key":"R8-14-20241201","doi-asserted-by":"crossref","first-page":"G497","DOI":"10.1152\/ajpgi.00171.2004","article-title":"Recent advances in alcoholic liver disease. 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