Regulation of cytokine-induced prostanoid and nitric oxide synthesis by extracellular signal&#x2013;regulated kinase 1/2 in lung epithelial cells.
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.
Rice
Pamela L
PL
Veterans Affairs Medical Center, Denver, Colorado, USA.
Barrett
Bradley S
BS
Fritz
Jason M
JM
Srebernak
Mary C
MC
Kisley
Lori R
LR
Malkinson
Alvin M
AM
Dwyer-Nield
Lori D
LD
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
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
Cancer Chemother Pharmacol. 2008 Sep;62(4):605-20
18030469
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
Cancer Prev Res (Phila). 2008 Oct;1(5):349-56
19138979
Nat Med. 2008 Dec;14(12):1351-6
19029981
J Clin Invest. 1997 Mar 1;99(5):1057-63
9062364
Clin Cancer Res. 2008 Jun 15;14(12):3651-6
18559577
Jpn J Cancer Res. 1997 Dec;88(12):1190-8
9473737
Nat Rev Cancer. 2001 Oct;1(1):11-21
11900248
Lung Cancer. 2003 Aug;41(2):123-30
12871775
J Immunol. 2001 Dec 1;167(11):6533-44
11714822
Clin Cancer Res. 2003 Jun;9(6):2241-7
12796392
Science. 2002 Jul 5;297(5578):63-4
12098689
J Biol Chem. 1998 Jul 24;273(30):18701-4
9668040
Genes Dev. 2005 Mar 15;19(6):643-64
15769940
J Biol Chem. 1998 Jan 30;273(5):3021-6
9446616
Chest. 2004 May;125(5 Suppl):141S
15136467
Cancer. 2003 Apr 1;97(7):1732-6
12655530
Anticancer Res. 2001 May-Jun;21(3B):1749-55
11497255
Lancet. 1977 Sep 10;2(8037):523-6
95731
Mol Carcinog. 1990;3(5):279-86
2244960
Cancer Res. 2006 Dec 1;66(23):11494-501
17145898
Ann Thorac Surg. 2003 Oct;76(4):1327-35
14530048
Mol Cancer Ther. 2003 Jul;2(7):641-9
12883037
Br J Cancer. 2004 Mar 8;90(5):1047-52
14997206
Cancer Lett. 2001 Jul 26;168(2):165-72
11403921
Cancer Res. 1998 Dec 1;58(23):5354-60
9850065
BMC Cancer. 2005 Nov 04;5:145
16271139
Cancer Res. 2005 Sep 15;65(18):8423-32
16166321
Oncogene. 2006 Jan 12;25(2):198-206
16116474
Anal Biochem. 2004 Nov 15;334(2):266-75
15494133
Cancer Res. 2002 Feb 1;62(3):734-40
11830527
Biochem Biophys Res Commun. 1994 Feb 15;198(3):835-43
7509602
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3014-9
9501207
J Cell Biol. 1975 Jul;66(1):188-93
49354
Cancer Res. 2004 Aug 15;64(16):5897-904
15313935
Carcinogenesis. 2000 Apr;21(4):543-50
10753183
Am J Physiol. 1998 Jun;274(6):L922-32
9609731
Cell Biol Int Rep. 1989 Sep;13(9):729-38
2680110
Cancer Prev Res (Phila). 2009 Jan;2(1):74-83
19139021
J Biol Chem. 1996 Dec 6;271(49):31742-8
8940199
Br J Cancer. 1998 Aug;78(4):534-41
9716040
Nature. 1995 Nov 16;378(6554):307-10
7477354
J Natl Cancer Inst. 2006 Jun 21;98(12):846-55
16788158
Am J Epidemiol. 1995 Jun 1;141(11):1023-32
7771438
Biochem J. 2000 Oct 1;351(Pt 1):95-105
10998351
Cancer Res. 2001 Feb 15;61(4):1541-7
11245463
Biochem J. 1996 Sep 15;318 ( Pt 3):797-803
8836122
J Exp Med. 1999 Jun 7;189(11):1707-14
10359574
Methods Mol Med. 2003;74:283-97
12415703
J Pharmacol Exp Ther. 1983 Jul;226(1):78-87
6345756
J Biol Chem. 2001 Mar 16;276(11):8445-52
11112784
Cytokine Growth Factor Rev. 2003 Dec;14(6):511-22
14563353
Br J Pharmacol. 1997 Mar;120(5):910-6
9138698
Cancer Res. 2002 Dec 1;62(23):6850-6
12460898
Carcinogenesis. 1997 May;18(5):1001-6
9163687
Int J Oncol. 2003 Mar;22(3):469-80
12579299
Clin Lung Cancer. 2003 Jul;5(1):46-62
14596704
Am J Pathol. 2005 Dec;167(6):1763-75
16314486
J Biol Chem. 1951 Nov;193(1):265-75
14907713
Toxicology. 1997 Nov 21;123(1-2):53-100
9347924
Carcinogenesis. 2005 Jul;26(7):1196-206
15746162