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It was hypothesized that the involvement of the MAPK pathway in regulating LPS\u2010mediated TNF\u2010\u03b1 secretion is redox\u2010dependent, NF\u2010\u03baB\u2010sensitive and attenuated by <jats:italic>N<\/jats:italic>\u2010acetyl\u2010<jats:sc>L<\/jats:sc>\u2010cysteine (NAC) and other antioxidants.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In alveolar epithelial cells, LPS induced a time\u2010 and dose\u2010dependent phosphorylation of MAPK<jats:sup>p38<\/jats:sup>. This was associated with the activation of MAPK\u2010activated protein kinase, which phosphorylated the small heat\u2010shock protein, Hsp27.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>MAPK<jats:sup>p38<\/jats:sup> inhibition (SB\u2010203580) abrogated LPS\u2010induced TNF\u2010\u03b1 production. MAPK<jats:sup>ERK<\/jats:sup> blockade (PD\u201098059) attenuated TNF\u2010\u03b1 secretion, an effect synergistically amplified in the presence of SB\u2010203580.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Regulation of NF\u2010\u03baB by selective inhibitors revealed that this pathway is partially involved in regulating LPS\u2010mediated TNF\u2010\u03b1 secretion. Whereas the proteasome inhibitor, MG\u2010132, had no effect on LPS\u2010mediated TNF\u2010\u03b1 production, CAPE, sulfasalazine and SN\u201050, a cell\u2010permeant NF\u2010\u03baB inhibitor, attenuated but did not abrogate TNF\u2010\u03b1 biosynthesis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LPS up\u2010regulated ROS, an effect abrogated by 4\u2032\u2010hydroxy\u20103\u2032\u2010methoxy\u2010acetophenone and NAC, which reduced TNF\u2010\u03b1 secretion, induced the accumulation of GSH, reduced the concentration of GSSG, and blockaded the phosphorylation\/activation of MAPK<jats:sup>p38<\/jats:sup> pathway.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>ROS induced MAPK<jats:sup>p38<\/jats:sup> phosphorylation and selective antioxidants, including the permeant GSH precursor, \u03b3\u2010GCE, reduced ROS\u2010dependent MAPK<jats:sup>p38<\/jats:sup> phosphorylation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results indicate that the MAPK pathway and MAPK\u2010mediated regulation of TNF\u2010\u03b1 production is redox\u2010dependent, GSH\u2010mediated and requires, at least in part, a NF\u2010\u03baB\/ROS\u2010sensitive mechanism.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2002) <jats:bold>135<\/jats:bold>, 520\u2013536; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0704467\">10.1038\/sj.bjp.0704467<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0704467","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T21:40:49Z","timestamp":1106948449000},"page":"520-536","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":150,"title":["Redox\/ROS regulation of lipopolysaccharide\u2010induced mitogen\u2010activated protein kinase (MAPK) activation and MAPK\u2010mediated TNF\u2010\u03b1 biosynthesis"],"prefix":"10.1111","volume":"135","author":[{"given":"J J","family":"Haddad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S C","family":"Land","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(89)90066-X"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.162.9.5367"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.14.1.649"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.280.5.H1970"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1999.8716"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(91)90284-5"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(00)88978-1"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.24.5.4280"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.20.11715"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.7.3951"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.20.2.385"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1367-5931(99)80068-4"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.8.14.7958618"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600594"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111558"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00096-0"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(99)80028-3"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-3003.1999.14a17.x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.9.5211"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)35980-5"},{"key":"e_1_2_7_22_1","first-page":"1070","article-title":"VX\u2010745 Vertex Pharmaceuticals: A novel MAPKp38 inhibitor with anti\u2010inflammatory actions","volume":"2","author":"HADDAD J.J.","year":"2001","journal-title":"Curr. 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