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• W2000691137 abstract "Increased expression of tumor necrosis factor α (TNFα) in response to chronic ethanol has been implicated in the pathogenesis of alcoholic liver disease. However, the molecular mechanisms by which ethanol increases the levels of TNFα are not well characterized. Utilizing Kupffer cells isolated from rats fed an ethanol containing diet and a murine macrophage cell line, RAW264.7, exposed to ethanol in culture, we have demonstrated that exposure to chronic ethanol results in an enhanced expression of lipopolysaccharide (LPS)-induced TNFα. While chronic ethanol had no effect on the rate of LPS-induced TNFα transcription as measured by nuclear run-on experiments, TNFα mRNA half-life was increased by chronic ethanol. Chronic ethanol also potentiated the activation of LPS-induced p38 mitogen-activated protein (MAP) kinase in Kupffer cells, as well as in RAW264.7 cells. Specific inhibition of p38 MAP kinase activation by SB203580 in Kupffer cells or by overexpression of dominant negative p38 MAP kinase in RAW264.7 cells blocked ethanol-mediated TNFα mRNA stabilization. Furthermore, using chimeric reporter constructs, we have shown that A + U-rich elements in the 3′-untranslated region of TNFα mRNA are not sufficient to impart ethanol-mediated stabilization on TNFα mRNA. Increased expression of tumor necrosis factor α (TNFα) in response to chronic ethanol has been implicated in the pathogenesis of alcoholic liver disease. However, the molecular mechanisms by which ethanol increases the levels of TNFα are not well characterized. Utilizing Kupffer cells isolated from rats fed an ethanol containing diet and a murine macrophage cell line, RAW264.7, exposed to ethanol in culture, we have demonstrated that exposure to chronic ethanol results in an enhanced expression of lipopolysaccharide (LPS)-induced TNFα. While chronic ethanol had no effect on the rate of LPS-induced TNFα transcription as measured by nuclear run-on experiments, TNFα mRNA half-life was increased by chronic ethanol. Chronic ethanol also potentiated the activation of LPS-induced p38 mitogen-activated protein (MAP) kinase in Kupffer cells, as well as in RAW264.7 cells. Specific inhibition of p38 MAP kinase activation by SB203580 in Kupffer cells or by overexpression of dominant negative p38 MAP kinase in RAW264.7 cells blocked ethanol-mediated TNFα mRNA stabilization. Furthermore, using chimeric reporter constructs, we have shown that A + U-rich elements in the 3′-untranslated region of TNFα mRNA are not sufficient to impart ethanol-mediated stabilization on TNFα mRNA. tumor necrosis factor α interleukin lipopolysaccharide RNase protection assay mitogen-activated protein extracellular regulated kinase stress activated protein kinase/c-Jun N-terminal kinase untranslated region A + U-rich elements cyclo-oxygenase-2 protein kinase C glyceraldehyde-3-phosphate dehydrogenase The inflammatory response is a key component of host defense. Macrophages participate in this tightly regulated process, at least in part, via the secretion of proinflammatory cytokines, such as tumor necrosis factor α (TNFα)1 and interleukin-1 (IL-1), in response to various stimuli encountered in the tissue microenvironment. TNFα is one of the principal mediators of the inflammatory response in mammals, transducing differential signals that regulate cellular activation and proliferation, cytotoxicity, and apoptosis (1Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar, 2Jacob C.O. Immunol. Today. 1992; 13: 122-125Abstract Full Text PDF PubMed Scopus (127) Google Scholar). In addition to its role in acute septic shock, TNFα has been implicated in the pathogenesis of a wide variety of inflammatory diseases (3Keffer J. Probert L. Cazlaris H. Georgopoulos S. Kaslaris E. Kioussis D. Kollias G. EMBO J. 1991; 10: 4025-4031Crossref PubMed Scopus (1330) Google Scholar, 4Reimund J.M. Wittersheim C. Dumont S. Muller C.D. Baumann R. Poindron P. Duclos B. J. Clin. Immunol. 1996; 16: 144-150Crossref PubMed Scopus (256) Google Scholar, 5Shalaby M.R. Fendly B. Sheehan K.C. Schreiber R.D. Ammann A.J. Transplantation. 1989; 47: 1057-1061Crossref PubMed Scopus (59) Google Scholar) as well as in the progression of alcoholic liver disease (6Akerman P. Cote P. Yang S.Q. McClain C. Nelson S. Bagby G.J. Diehl A.M. Am. J. Physiol. 1992; 263: G579-585Crossref PubMed Google Scholar, 7Cressman D.E. Greenbaum L.E. DeAngelis R.A. Ciliberto G. Furth E.E. Poli V. Taub R. Science. 1996; 274: 1379-1383Crossref PubMed Scopus (1302) Google Scholar, 8Thurman R.G. Am. J. Physiol. 1998; 275: G605-G611PubMed Google Scholar, 9Tilg H. Diehl A.M. N. Engl. J. Med. 2000; 343: 1467-1476Crossref PubMed Scopus (830) Google Scholar). Data from a number of animal studies, in combination with clinical studies, indicate that long-term alcohol consumption results in the development of fatty liver and steatohepatitis with progression to more severe liver damage including fibrosis, cirrhosis, and hepatocellular carcinoma (9Tilg H. Diehl A.M. N. Engl. J. Med. 2000; 343: 1467-1476Crossref PubMed Scopus (830) Google Scholar). At least some of these alcohol-induced liver abnormalities have been linked to the overexpression of TNFα. Indeed, enhanced levels of TNFα have been observed in the liver of ethanol-fed animals, as well as in the circulation of patients with alcoholic liver disease (10Bode C. Kugler V. Bode J.C. J. Hepatol. 1987; 4: 8-14Abstract Full Text PDF PubMed Scopus (457) Google Scholar, 11Fukui H. Brauner B. Bode J. Bode C. J. Hepatol. 1991; 12: 162-169Abstract Full Text PDF PubMed Scopus (402) Google Scholar). However, the molecular mechanisms leading to this overexpression in response to alcohol are poorly understood.Considering the pleiotropic actions of TNFα, it is not surprising that its biosynthesis is under the control of multiple and complex regulatory mechanisms. TNFα expression is regulated at transcriptional, post-transcriptional, as well as translational levels (1Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar, 2Jacob C.O. Immunol. Today. 1992; 13: 122-125Abstract Full Text PDF PubMed Scopus (127) Google Scholar, 12Jacob C.O. Lee S.K. Strassmann G. J. Immunol. 1996; 156: 3043-3050PubMed Google Scholar). Modulation of mRNA stability is an important mechanism of TNFα biosynthesis (12Jacob C.O. Lee S.K. Strassmann G. J. Immunol. 1996; 156: 3043-3050PubMed Google Scholar, 13Hel Z. Skamene E. Radzioch D. Mol. Cell. Biol. 1996; 16: 5579-5590Crossref PubMed Scopus (46) Google Scholar). Stabilization of mRNAs contributes to the strong and rapid induction of genes in the inflammatory process. Although the mechanisms involved in post-transcriptional gene regulation are complex, the mRNA itself contains sequence-specific information that determines its stability (14Sachs A.B. Cell. 1993; 74: 413-421Abstract Full Text PDF PubMed Scopus (771) Google Scholar, 15Ross J. Microbiol. Rev. 1995; 59: 423-450Crossref PubMed Google Scholar, 16Shaw G. Kamen R. Cell. 1986; 46: 659-667Abstract Full Text PDF PubMed Scopus (3107) Google Scholar). TNFα mRNA, like other short-lived mRNAs, contains A + U-rich elements (ARE) in its 3′-untranslated region (UTR) which function as destabilizing elements as demonstrated in TNFα-ARE knockout mouse in vivo (17Kontoyiannis D. Pasparakis M. Pizarro T.T. Cominelli F. Kollias G. Immunity. 1999; 10: 387-398Abstract Full Text Full Text PDF PubMed Scopus (1092) Google Scholar), as well as in various in vitro systems (13Hel Z. Skamene E. Radzioch D. Mol. Cell. Biol. 1996; 16: 5579-5590Crossref PubMed Scopus (46) Google Scholar,18Lagnado C.A. Brown C.Y. Goodall G.J. Mol. Cell. Biol. 1994; 14: 7984-7995Crossref PubMed Scopus (310) Google Scholar). AREs have also been implicated in stimulus-induced stabilization of otherwise unstable mRNAs (19Tebo J.M. Datta S. Kishore R. Kolosov M. Major J.A. Ohmori Y. Hamilton T.A. J. Biol. Chem. 2000; 275: 12987-12993Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 20Winzen R. Kracht M. Ritter B. Wilhelm A. Chen C.Y. Shyu A.B. Muller M. Gaestel M. Resch K. Holtmann H. EMBO J. 1999; 18: 4969-4980Crossref PubMed Scopus (708) Google Scholar). Sequences in the 5′-UTRs or coding regions, acting either in concert with AREs in the 3′-UTR or independently, also contribute to mRNA stabilization of certain genes (19Tebo J.M. Datta S. Kishore R. Kolosov M. Major J.A. Ohmori Y. Hamilton T.A. J. Biol. Chem. 2000; 275: 12987-12993Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 21Chen C.Y. Del Gatto-Konczak F. Wu Z. Karin M. Science. 1998; 280: 1945-1949Crossref PubMed Scopus (329) Google Scholar). However, the signaling pathways involved in the control of mRNA stabilization are not well defined.Proinflammatory cytokines and external stressors act through receptor-dependent signaling cascades that diverge into multiple pathways, including the NFκB pathway (22Baldwin Jr., A.S. Annu. Rev. Immunol. 1996; 14: 649-683Crossref PubMed Scopus (5542) Google Scholar) and each of the three mitogen-activated protein (MAP) kinases: extracellular-regulated kinase (ERK), stress-activated protein kinase/c-jun N-terminal kinase (SAPK/JNK), and p38 MAP kinase (23Karin M. Ann. N. Y. Acad. Sci. 1998; 851: 139-146Crossref PubMed Scopus (289) Google Scholar, 24Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2249) Google Scholar). While each of these signaling pathways contributes to the activation of gene transcription (22Baldwin Jr., A.S. Annu. Rev. Immunol. 1996; 14: 649-683Crossref PubMed Scopus (5542) Google Scholar, 25Karin M. Liu Z. Zandi E. Curr. Opin. Cell Biol. 1997; 9: 240-246Crossref PubMed Scopus (2280) Google Scholar), their role in controlling gene expression at the level of mRNA stability is not well understood. Although some studies have shown the involvement of ERK1/2 and SAPK/JNK pathways in the mRNA stability (21Chen C.Y. Del Gatto-Konczak F. Wu Z. Karin M. Science. 1998; 280: 1945-1949Crossref PubMed Scopus (329) Google Scholar, 26Lee N.H. Malek R.L. J. Biol. Chem. 1998; 273: 22317-22325Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 27Ming X.F. Kaiser M. Moroni C. EMBO J. 1998; 17: 6039-6048Crossref PubMed Scopus (137) Google Scholar, 28Xu K. Robida A.M. Murphy T.J. J. Biol. Chem. 2000; 275: 23012-23019Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), the majority of studies suggest that mRNAs encoding for proinflammatory genes including, cyclooxygenase-2 (COX-2), IL-6, IL-8, and TNFα, are stabilized upon activation of the p38 MAP kinase pathway (20Winzen R. Kracht M. Ritter B. Wilhelm A. Chen C.Y. Shyu A.B. Muller M. Gaestel M. Resch K. Holtmann H. EMBO J. 1999; 18: 4969-4980Crossref PubMed Scopus (708) Google Scholar, 29Brook M. Sully G. Clark A.R. Saklatvala J. FEBS Lett. 2000; 483: 57-61Crossref PubMed Scopus (193) Google Scholar, 30Dean J.L. Wait R. Mahtani K.R. Sully G. Clark A.R. Saklatvala J. Mol. Cell. Biol. 2001; 21: 721-730Crossref PubMed Scopus (245) Google Scholar). This p38 MAP kinase-mediated stabilization is dependent on ARE sequences in the 3′-UTRs of respective genes (20Winzen R. Kracht M. Ritter B. Wilhelm A. Chen C.Y. Shyu A.B. Muller M. Gaestel M. Resch K. Holtmann H. EMBO J. 1999; 18: 4969-4980Crossref PubMed Scopus (708) Google Scholar, 29Brook M. Sully G. Clark A.R. Saklatvala J. FEBS Lett. 2000; 483: 57-61Crossref PubMed Scopus (193) Google Scholar,31Lasa M. Brook M. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2001; 21: 771-780Crossref PubMed Scopus (216) Google Scholar). Thus, while AREs confer instability on mRNAs, they also allow mRNA stabilization following activation of p38 MAPK pathway (30Dean J.L. Wait R. Mahtani K.R. Sully G. Clark A.R. Saklatvala J. Mol. Cell. Biol. 2001; 21: 721-730Crossref PubMed Scopus (245) Google Scholar).Despite the suggested role of TNFα in the pathogenesis of alcoholic liver disease, the mechanisms by which chronic alcohol exposure increases TNFα expression are not well understood. Ethanol modulates the activity of several important signaling molecules (32Diamond I. Gordon A.S. Physiol. Rev. 1997; 77: 1-20Crossref PubMed Scopus (315) Google Scholar) including ERK1/2, p38 MAPK (33Chen J.P. Ishac E.J.N. Dent P. Kunos G. Gao B. Biochem. J. 1998; 334: 669-676Crossref PubMed Scopus (99) Google Scholar), JNK (33Chen J.P. Ishac E.J.N. Dent P. Kunos G. Gao B. Biochem. J. 1998; 334: 669-676Crossref PubMed Scopus (99) Google Scholar, 34Roivainen R. Hundle B. Messing R.O. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1891-1895Crossref PubMed Scopus (79) Google Scholar), and the transcription factors NFκB (35Zeldin G. Yang S.Q. Yin M. Lin H.Z. Rai R. Diehl A.M. Alcohol. Clin. Exp. Res. 1996; 20: 1639-1645Crossref PubMed Scopus (55) Google Scholar) and Egr-1. 2L. Shi, R. Kishore, M. R. McMullen, and L. E. Nagy, submitted for publication.2L. Shi, R. Kishore, M. R. McMullen, and L. E. Nagy, submitted for publication.However, it is not known whether ethanol-induced changes in these pathways contribute to abnormal TNFα transcription and/or translation.To investigate the mechanism for ethanol-mediated increases in TNFα, we have studied the effect of chronic ethanol in the regulation of LPS-induced TNFα expression, both in Kupffer cells isolated from ethanol-fed rats, as well as in a mouse macrophage like cell line, RAW264.7, exposed to chronic ethanol in culture. We demonstrate, for the first time, that ethanol stabilizes LPS-induced TNFα mRNA. We further demonstrate that activation of p38 MAP kinase pathway is required for the ethanol-mediated TNFα mRNA stabilization, but that the AREs in the TNFα-3′-UTR are not sufficient to mediate ethanol-induced stabilization of TNFα mRNA.DISCUSSIONAlthough enhanced expression of TNFα has been implicated in the pathogenesis of alcoholic liver disease, the molecular mechanisms regulating TNFα overexpression are not well understood. In the present study, utilizing an ethanol-fed rat model, as well as mouse macrophage cells exposed to ethanol in culture, we have demonstrated that chronic ethanol specifically increases the LPS-induced TNFα mRNA stability. Furthermore, stabilization of TNFα mRNA by ethanol was dependent on activation of p38 MAP kinase, but independent of the ARE sequences in the 3′-UTR of the TNFα mRNA. Chronic ethanol specifically enhanced the accumulation of TNFα; this specific increase in TNFα mRNA level was observed both in mouse RAW264.7 macrophage cells after in vitro exposure to ethanol and in Kupffer cells isolated from rats fed ethanol in vivo. Furthermore, in both types of macrophages, chronic ethanol increased the half-life of LPS-induced TNFα mRNA, without affecting the rate of TNFα transcription. Increased stability of TNFα mRNA was directly associated with an increase in LPS-induced activation of p38 MAP kinase; inhibition of p38 MAP kinase activation by two different approaches blocked the ethanol-mediated stabilization of TNFα mRNA, while inhibition of ERK1/2 activation did not affect TNFα mRNA stability. Moreover, AREs in the 3′-UTR of TNFα mRNA destabilized luciferase reporter mRNA but were not sufficient to render ethanol-mediated stabilization on the transgene.There is now general agreement that long-term alcohol consumption leads to an increased expression of TNFα in liver. It has been suggested that chronic ethanol consumption compromises the barrier function of gastrointestinal mucosa, overexposing liver cells to endotoxins, such as LPS, and resulting in an increased TNFα production (40Bickel M. Cohen R.B. Pluznik D.H. J. Immunol. 1990; 145: 840-845PubMed Google Scholar, 41Honchel R. Marsono L. Cohen D. Shedlofsky S. McClain C. Dinarello C.A. Kluger M.J. Powanda M.C. Oppenheim J.J. The Physiological and Pathological Effects of Cytokines. 10B. Wiley-Liss, New York1990: 171-176Google Scholar, 42Mathurin P. Deng Q.G. Keshavarzian A. Choudhary S. Holmes E.W. Tsukamoto H. Hepatology. 2000; 32: 1008-1017Crossref PubMed Scopus (251) Google Scholar). Indeed, ethanol-induced liver injury was blunted by treating ethanol-fed rats with antibiotics, further supporting the association of endotoxins with the ethanol-induced liver injury (43Adachi Y. Moore L.E. Bradford B.U. Gao W. Thurman R.G. Gastroenterology. 1995; 108: 218-224Abstract Full Text PDF PubMed Scopus (592) Google Scholar). However, little is known about the mechanism by which chronic ethanol up-regulates LPS-induced expression of proinflammatory mediators including TNFα. Our data show that ethanol specifically enhanced TNFα mRNA level in rat Kupffer cells, but did not increase the accumulation of other proinflammatory cytokines (Fig. 1). Interestingly, chronic ethanol decreased the LPS-induced mRNA accumulation of IL-1β. IL-1β expression is regulated by many of the mechanisms as TNFα, involving modulation of gene transcription, mRNA stability and mRNA translation (44Holtmann H. Winzen R. Holland P. Eickemeier S. Hoffmann E. Wallach D. Malinin N.L. Cooper J.A. Resch K. Kracht M. Mol. Cell. Biol. 1999; 19: 6742-6753Crossref PubMed Scopus (268) Google Scholar, 45Saklatvala J. Dean J. Finch A. Biochem. Soc. Symp. 1999; 64: 63-77PubMed Google Scholar). Thus, the differential effect of chronic ethanol on LPS-induced mRNA expression of TNFα and IL-1β in Kupffer cells suggests that chronic ethanol must impact on distinct molecular mechanisms and signaling pathways to differentially regulate the expression of TNFα compared with IL-1β.Cell type and stimulus specific transcriptional regulation of TNFα has been reported in a number of studies (1Beutler B. J. Invest. Med. 1995; 43: 227-235PubMed Google Scholar, 2Jacob C.O. Immunol. Today. 1992; 13: 122-125Abstract Full Text PDF PubMed Scopus (127) Google Scholar, 46Pauli U. Crit. Rev. Eukaryotic Gene Exp. 1994; 4: 323-344Crossref PubMed Scopus (38) Google Scholar). We have recently demonstrated that exposure of RAW264.7 macrophages to chronic ethanol modulates the LPS-induced DNA binding activity of at least two transcription factors to the TNFα promoter. Chronic ethanol increases Egr-1 binding activity, but decreases the binding activity of NFκB.2 However, in the present study, we found no discernible changes in the rate of de novo transcribed TNFα in response to chronic ethanol (Fig. 2). These results indicate that despite multiple effects on DNA binding activity of key transcription factors, there is no net effect on the rate of TNFα transcription in response to chronic ethanol and that post-transcriptional mechanism(s) must contribute to ethanol-mediated up-regulation of TNFα mRNA.Chronic ethanol stabilized the LPS-induced TNFα mRNA both in a mouse macrophage cell line RAW264.7 and in Kupffer cells isolated from rats fed ethanol for 4 weeks (Fig. 3). Utilizing a wide variety of cell types, several studies have shown stimulus-specific stabilization of otherwise labile mRNAs that contributes to a rapid increase in their abundance. Phorbol ester treatment increases the half-life of granulocyte macrophage-colony stimulating factor mRNA (16Shaw G. Kamen R. Cell. 1986; 46: 659-667Abstract Full Text PDF PubMed Scopus (3107) Google Scholar, 47Bjarnason I. Ward K. Peters T.J. Lancet. 1984; 1: 179-182Abstract PubMed Scopus (379) Google Scholar). Calcium ionophore transiently stabilizes IL-3 mRNA in a murine mast cell line (48Wodnar-Filipowicz A. Moroni C. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 777-781Crossref PubMed Scopus (131) Google Scholar). In T cells, IL-2 mRNA is stabilized by co-stimulatory signal through CD-28, upon stimulation of T cell receptor (49Lindstein T. June C.H. Ledbetter J.A. Stella G. Thompson C.B. Science. 1989; 244: 339-343Crossref PubMed Scopus (801) Google Scholar). More recently a number of studies have shown the stimulus-induced stabilization of COX-2, IL-6, IL-8, GROα, MCP-1, and TNFα mRNAs in macrophage/monocytes, as well as in other cell types (19Tebo J.M. Datta S. Kishore R. Kolosov M. Major J.A. Ohmori Y. Hamilton T.A. J. Biol. Chem. 2000; 275: 12987-12993Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 20Winzen R. Kracht M. Ritter B. Wilhelm A. Chen C.Y. Shyu A.B. Muller M. Gaestel M. Resch K. Holtmann H. EMBO J. 1999; 18: 4969-4980Crossref PubMed Scopus (708) Google Scholar, 28Xu K. Robida A.M. Murphy T.J. J. Biol. Chem. 2000; 275: 23012-23019Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 29Brook M. Sully G. Clark A.R. Saklatvala J. FEBS Lett. 2000; 483: 57-61Crossref PubMed Scopus (193) Google Scholar, 31Lasa M. Brook M. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2001; 21: 771-780Crossref PubMed Scopus (216) Google Scholar, 50Rovin B.H. Wilmer W.A. Danne M. Dickerson J.A. Dixon C.L. Lu L. Cytokine. 1999; 11: 118-126Crossref PubMed Scopus (67) Google Scholar). However, this is the first study to demonstrate ethanol-mediated modulation of TNFα stability in any cell type. Whether this phenomenon is a more generalized effect of ethanol or is restricted to macrophages remains to be elucidated.LPS is known to activate all members of the MAP kinase family. To gain insight into the role of MAP kinase signaling pathways in the ethanol-mediated stabilization of TNFα transcript, we studied the effect of chronic ethanol on the LPS-induced phosphorylation of p38 and ERK1/2 MAP kinases. Chronic ethanol exposure increased LPS stimulated phosphorylation of p38 MAP kinase (Fig. 5). This observation is consistent with a number of other studies reporting the effect of ethanol on MAP kinase activation. Ethanol exposure, both long- and short-term, potentiates agonist-induced activation of p38, ERK1/2, as well as SAPK/JNK MAP kinases in hepatocytes (33Chen J.P. Ishac E.J.N. Dent P. Kunos G. Gao B. Biochem. J. 1998; 334: 669-676Crossref PubMed Scopus (99) Google Scholar, 34Roivainen R. Hundle B. Messing R.O. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1891-1895Crossref PubMed Scopus (79) Google Scholar). Long-term ethanol exposure increases NGF-stimulated ERK1/2 in PC12 cells (41Honchel R. Marsono L. Cohen D. Shedlofsky S. McClain C. Dinarello C.A. Kluger M.J. Powanda M.C. Oppenheim J.J. The Physiological and Pathological Effects of Cytokines. 10B. Wiley-Liss, New York1990: 171-176Google Scholar). In NIH 3T3 fibroblasts, ethanol potentiates sphingosine-1 phosphate-stimulated ERK1/2 activation, but not p38 MAP kinase (51Huang J.S. Mukherjee J.J. Kiss Z. Arch. Biochem. Biophys. 1999; 366: 131-138Crossref PubMed Scopus (12) Google Scholar). More recently we have shown that in RAW264.7 mouse macrophage cells, chronic ethanol increases LPS-stimulated phosphorylation of ERK1/2 MAP kinases.2 The mechanism by which ethanol potentiates LPS-stimulated activation of p38 remains an unresolved question. Since chronic ethanol increases both LPS-stimulated ERK1/2 and p38, we are currently investigating whether ethanol acts at a common upstream signaling intermediate linking LPS-receptor activation to both these members of the MAP kinase family. Alternatively, ethanol could also enhance ERK1/2 and p38 activity by decreasing MAP kinase phosphatase-1 activity, which can inactivate both phosphorylated ERK1/2 and p38.There is growing body of evidence indicating the participation of MAP kinases in stimulus-induced stabilization of various short-lived transcripts. Studies on the signaling pathways involved in mRNA stability have shown p38, ERK1/2, SAPK/JNK MAP kinases, as well as cAMP-dependent protein kinase A, are important contributors to this post-transcriptional regulatory mechanism (21Chen C.Y. Del Gatto-Konczak F. Wu Z. Karin M. Science. 1998; 280: 1945-1949Crossref PubMed Scopus (329) Google Scholar, 28Xu K. Robida A.M. Murphy T.J. J. Biol. Chem. 2000; 275: 23012-23019Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 52Xu K. Murphy T.J. J. Biol. Chem. 2000; 275: 7604-7611Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). The emerging picture from these studies suggests that stabilization of mRNAs can be achieved by different signaling events; effectors of multiple signaling cascades impact on the pathways regulating mRNA decay. These effectors can, therefore, connect changes in the extracellular environment to the post-transcriptional control of gene expression. Here we have shown that inhibition of p38 MAP kinase specifically abrogates the ethanol-mediated stabilization of the TNFα transcript (Figs. 6 and 7). p38 MAP kinase has been implicated in the regulation of mRNA stability in other systems as well. For example, while maximal IL-8 gene expression requires activation of all three MAP kinases, the p38 MAP kinase pathway selectively stabilizes IL-8 mRNA (44Holtmann H. Winzen R. Holland P. Eickemeier S. Hoffmann E. Wallach D. Malinin N.L. Cooper J.A. Resch K. Kracht M. Mol. Cell. Biol. 1999; 19: 6742-6753Crossref PubMed Scopus (268) Google Scholar). Similarly, COX-2 mRNA stabilization in HeLa cells involves activation of p38 MAP kinase (31Lasa M. Brook M. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2001; 21: 771-780Crossref PubMed Scopus (216) Google Scholar). Stimulus-induced stabilization of mRNAs encoding for COX-2 (30Dean J.L. Wait R. Mahtani K.R. Sully G. Clark A.R. Saklatvala J. Mol. Cell. Biol. 2001; 21: 721-730Crossref PubMed Scopus (245) Google Scholar, 53Jang B.C. Sanchez T. Schaefers H.J. Trifan O.C. Liu C.H. Creminon C. Huang C.K. Hla T. J. Biol. Chem. 2000; 275: 39507-39515Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 54Ridley S.H. Dean J.L. Sarsfield S.J. Brook M. Clark A.R. Saklatvala J. FEBS Lett. 1998; 439: 75-80Crossref PubMed Scopus (201) Google Scholar), IL-6 (20Winzen R. Kracht M. Ritter B. Wilhelm A. Chen C.Y. Shyu A.B. Muller M. Gaestel M. Resch K. Holtmann H. EMBO J. 1999; 18: 4969-4980Crossref PubMed Scopus (708) Google Scholar), platelet-derived growth factor receptor α (55Wang Y.Z. Zhang P. Rice A.B. Bonner J.C. J. Biol. Chem. 2000; 275: 22550-22557Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), MCP-1 (50Rovin B.H. Wilmer W.A. Danne M. Dickerson J.A. Dixon C.L. Lu L. Cytokine. 1999; 11: 118-126Crossref PubMed Scopus (67) Google Scholar), erythropoetin (56Tamura K. Sudo T. Senftleben U. Dadak A.M. Johnson R. Karin M. Cell. 2000; 102: 221-231Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar), GROα, IL-1β (48Wodnar-Filipowicz A. Moroni C. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 777-781Crossref PubMed Scopus (131) Google Scholar), and TNFα (29Brook M. Sully G. Clark A.R. Saklatvala J. FEBS Lett. 2000; 483: 57-61Crossref PubMed Scopus (193) Google Scholar) is mediated via activation of the p38 MAP kinase. The ERK1/2 and SAPK/JNK pathways have also been shown to participate in mRNA stabilization (21Chen C.Y. Del Gatto-Konczak F. Wu Z. Karin M. Science. 1998; 280: 1945-1949Crossref PubMed Scopus (329) Google Scholar,26Lee N.H. Malek R.L. J. Biol. Chem. 1998; 273: 22317-22325Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 27Ming X.F. Kaiser M. Moroni C. EMBO J. 1998; 17: 6039-6048Crossref PubMed Scopus (137) Google Scholar, 28Xu K. Robida A.M. Murphy T.J. J. Biol. Chem. 2000; 275: 23012-23019Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Although chronic ethanol potentiates LPS-induced ERK1/2 phosphorylation in RAW264.7 cells,2 inhibition of ERK1/2 activation either by the specific inhibitor PD98059 or by kinase-dead dominant negative ERK1/2 has no effect on stability of TNFα mRNA (Figs. 6 and 7). Taken together, our data clearly show that although ethanol can potentiate the LPS-induced activation of both p38 and ERK1/2 MAP kinases, only p38 MAP kinase participates in ethanol-mediated stabilization of the TNFα mRNA.AREs present in the 3′-UTR of cytokine genes are well documented to mediate destabilization and/or stimulus-dependent stabilization of their respective mRNAs (14Sachs A.B. Cell. 1993; 74: 413-421Abstract Full Text PDF PubMed Scopus (771) Google Scholar, 15Ross J. Microbiol. Rev. 1995; 59: 423-450Crossref PubMed Google Scholar, 16Shaw G. Kamen R. Cell. 1986; 46: 659-667Abstract Full Text PDF PubMed Scopus (3107) Google Scholar). In most systems studied to date, AREs in the 3′-UTR of corresponding genes mediate stimulus-induced stabilization of the transcripts via p38 MAP kinase pathway (29Brook M. Sully G. Clark A.R. Saklatvala J. FEBS Lett. 2000; 483: 57-61Crossref PubMed Scopus (193) Google Scholar, 31Lasa M. Brook M. Saklatvala J. Clark A.R. Mol. Cell. Biol. 2001; 21: 771-780Crossref PubMed Scopus (216) Google Scholar, 54Ridley S.H. Dean J.L. Sarsfield S.J. Brook M. Clark A.R. Saklatvala J. FEBS Lett. 1998; 439: 75-80Crossref PubMed Scopus (201) Google Scholar, 57Sirenko O.I. Lofquist A.K. DeMaria C.T. Morris J.S. Brewer G. Haskill J.S. Mol. Cell. Biol. 1997; 17: 3898-3906Crossref PubMed Scopus (135) Google Scholar). Activation of the p38 MAP kinase stabilizes reporter β-globin mRNAs containing ARE sequences in the 3′-UTRs of IL-6, IL-8, c-fos, and granulocyte macrophage-colony stimulating factor, respectively (20Winzen R. Kracht M. Ritter B. Wilhelm A. Chen C.Y. Shyu A.B. Muller M. Gaestel M. Resch K. Holtmann H. EMBO J. 1999; 18: 4969-4980Crossref PubMed Scopus (708) Google Scholar). Therefore, we studied the requirement of the TNFα ARE sequences in the destabilization and ethanol-mediated stabilization of reporter luciferase mRNA. As expected, the TNFα AREs destabilized reporter mRNA. We, however, saw no evidence that TNFα AREs are involved in ethanol-mediated stabilization of the reporter luciferase mRNA. Although data presented in this study do not rule out the necessity of TNFα ARE sequences, nevertheless, they indicate that the TNFα AREs are not sufficient to modulate ethanol-mediated stabilization of the transcript. There are other examples where regulation of mRNA stability is determined not only by the ARE sequences in the 3′-UTR, but also by additional sequences found either in 5′-UTR or within the coding region of the corres" @default.
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• W2000691137 title "Stabilization of Tumor Necrosis Factor α mRNA by Chronic Ethanol" @default.
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