title: Regulation of cytokine-induced prostanoid and nitric oxide synthesis by extracellular signal&#x2013;regulated kinase 1/2 in lung epithelial cells.
abstract: The inflammatory cytokines tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) stimulate production of the inflammatory mediators prostaglandin E₂ (PGEγ), prostacyclin (PGIγ), and nitric oxide (NO) in cultured lung epithelial cells. Pretreatment of these cells with the selective MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase [ERK] kinase 1/2) inhibitor U0126 blocked ERK1/2 activation and inhibited cytokine-induced production of these inflammatory mediators. Primary bronchiolar epithelial Clara cells treated with TNFα and IFNγ also produced increased PGE₂, PGI₂, and NO, and PG and NO production was decreased by MEK inhibition. U0126 differentially affected cyclooxygenase (COX)-1, COX-2, and inducible NO synthase (iNOS) expression in cell lines, however, suggesting that MEK1/2 regulates prostanoid and NO production by means other than inducing their biosynthetic enzymes. Functionally, inhibition of MEK1/2 caused G1 cell cycle arrest and decreased cyclin D1 expression, but these effects were not related to decreased prostanoid production. These results indicate separate proinflammatory and proliferative roles for ERK1/2 in lung epithelial cells. During lung tumor formation in vivo, ERK1/2 phosphorylation increased as lung tumors progressed. Since tumor-derived cells were more sensitive than nontumorigenic cells to the antiproliferative effects of U0126, MEK1/2 inhibition may serve as an attractive chemotherapeutic target.
authors.affiliation: Veterans Affairs Medical Center, Denver, Colorado, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Rice
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Barrett
authors.forename: Jason M
authors.initials: JM
authors.lastname: Fritz
authors.forename: Mary C
authors.initials: MC
authors.lastname: Srebernak
authors.forename: Lori R
authors.initials: LR
authors.lastname: Kisley
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Malkinson
authors.forename: Lori D
authors.initials: LD
authors.lastname: Dwyer-Nield
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000096:biosynthesis*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011453:Prostaglandins / Q000096:biosynthesis*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D009569:Nitric Oxide; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases
references.citation: Cancer Chemother Pharmacol. 2008 Sep;62(4):605-20
references.pmid: 18030469
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Cancer Prev Res (Phila). 2008 Oct;1(5):349-56
references.pmid: 19138979
references.citation: Nat Med. 2008 Dec;14(12):1351-6
references.pmid: 19029981
references.citation: J Clin Invest. 1997 Mar 1;99(5):1057-63
references.pmid: 9062364
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3651-6
references.pmid: 18559577
references.citation: Jpn J Cancer Res. 1997 Dec;88(12):1190-8
references.pmid: 9473737
references.citation: Nat Rev Cancer. 2001 Oct;1(1):11-21
references.pmid: 11900248
references.citation: Lung Cancer. 2003 Aug;41(2):123-30
references.pmid: 12871775
references.citation: J Immunol. 2001 Dec 1;167(11):6533-44
references.pmid: 11714822
references.citation: Clin Cancer Res. 2003 Jun;9(6):2241-7
references.pmid: 12796392
references.citation: Science. 2002 Jul 5;297(5578):63-4
references.pmid: 12098689
references.citation: J Biol Chem. 1998 Jul 24;273(30):18701-4
references.pmid: 9668040
references.citation: Genes Dev. 2005 Mar 15;19(6):643-64
references.pmid: 15769940
references.citation: J Biol Chem. 1998 Jan 30;273(5):3021-6
references.pmid: 9446616
references.citation: Chest. 2004 May;125(5 Suppl):141S
references.pmid: 15136467
references.citation: Cancer. 2003 Apr 1;97(7):1732-6
references.pmid: 12655530
references.citation: Anticancer Res. 2001 May-Jun;21(3B):1749-55
references.pmid: 11497255
references.citation: Lancet. 1977 Sep 10;2(8037):523-6
references.pmid: 95731
references.citation: Mol Carcinog. 1990;3(5):279-86
references.pmid: 2244960
references.citation: Cancer Res. 2006 Dec 1;66(23):11494-501
references.pmid: 17145898
references.citation: Ann Thorac Surg. 2003 Oct;76(4):1327-35
references.pmid: 14530048
references.citation: Mol Cancer Ther. 2003 Jul;2(7):641-9
references.pmid: 12883037
references.citation: Br J Cancer. 2004 Mar 8;90(5):1047-52
references.pmid: 14997206
references.citation: Cancer Lett. 2001 Jul 26;168(2):165-72
references.pmid: 11403921
references.citation: Cancer Res. 1998 Dec 1;58(23):5354-60
references.pmid: 9850065
references.citation: BMC Cancer. 2005 Nov 04;5:145
references.pmid: 16271139
references.citation: Cancer Res. 2005 Sep 15;65(18):8423-32
references.pmid: 16166321
references.citation: Oncogene. 2006 Jan 12;25(2):198-206
references.pmid: 16116474
references.citation: Anal Biochem. 2004 Nov 15;334(2):266-75
references.pmid: 15494133
references.citation: Cancer Res. 2002 Feb 1;62(3):734-40
references.pmid: 11830527
references.citation: Biochem Biophys Res Commun. 1994 Feb 15;198(3):835-43
references.pmid: 7509602
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3014-9
references.pmid: 9501207
references.citation: J Cell Biol. 1975 Jul;66(1):188-93
references.pmid: 49354
references.citation: Cancer Res. 2004 Aug 15;64(16):5897-904
references.pmid: 15313935
references.citation: Carcinogenesis. 2000 Apr;21(4):543-50
references.pmid: 10753183
references.citation: Am J Physiol. 1998 Jun;274(6):L922-32
references.pmid: 9609731
references.citation: Cell Biol Int Rep. 1989 Sep;13(9):729-38
references.pmid: 2680110
references.citation: Cancer Prev Res (Phila). 2009 Jan;2(1):74-83
references.pmid: 19139021
references.citation: J Biol Chem. 1996 Dec 6;271(49):31742-8
references.pmid: 8940199
references.citation: Br J Cancer. 1998 Aug;78(4):534-41
references.pmid: 9716040
references.citation: Nature. 1995 Nov 16;378(6554):307-10
references.pmid: 7477354
references.citation: J Natl Cancer Inst. 2006 Jun 21;98(12):846-55
references.pmid: 16788158
references.citation: Am J Epidemiol. 1995 Jun 1;141(11):1023-32
references.pmid: 7771438
references.citation: Biochem J. 2000 Oct 1;351(Pt 1):95-105
references.pmid: 10998351
references.citation: Cancer Res. 2001 Feb 15;61(4):1541-7
references.pmid: 11245463
references.citation: Biochem J. 1996 Sep 15;318 ( Pt 3):797-803
references.pmid: 8836122
references.citation: J Exp Med. 1999 Jun 7;189(11):1707-14
references.pmid: 10359574
references.citation: Methods Mol Med. 2003;74:283-97
references.pmid: 12415703
references.citation: J Pharmacol Exp Ther. 1983 Jul;226(1):78-87
references.pmid: 6345756
references.citation: J Biol Chem. 2001 Mar 16;276(11):8445-52
references.pmid: 11112784
references.citation: Cytokine Growth Factor Rev. 2003 Dec;14(6):511-22
references.pmid: 14563353
references.citation: Br J Pharmacol. 1997 Mar;120(5):910-6
references.pmid: 9138698
references.citation: Cancer Res. 2002 Dec 1;62(23):6850-6
references.pmid: 12460898
references.citation: Carcinogenesis. 1997 May;18(5):1001-6
references.pmid: 9163687
references.citation: Int J Oncol. 2003 Mar;22(3):469-80
references.pmid: 12579299
references.citation: Clin Lung Cancer. 2003 Jul;5(1):46-62
references.pmid: 14596704
references.citation: Am J Pathol. 2005 Dec;167(6):1763-75
references.pmid: 16314486
references.citation: J Biol Chem. 1951 Nov;193(1):265-75
references.pmid: 14907713
references.citation: Toxicology. 1997 Nov 21;123(1-2):53-100
references.pmid: 9347924
references.citation: Carcinogenesis. 2005 Jul;26(7):1196-206
references.pmid: 15746162