title: Proinflammatory cytokines in heart failure: double-edged swords.
abstract: Increased circulating and intracardiac levels of proinflammatory cytokines have been associated with chronic heart failure. Following an initial insult, the increased production of proinflammatory cytokines, including TNF-α, IL-6, IL-1, and IL-18, jeopardizes the surrounding tissue through propagation of the inflammatory response and direct effects on the cardiac myocyte structure and function. Cardiac myocyte hypertrophy, contractile dysfunction, cardiac myocyte apoptosis, and extracellular matrix remodeling contribute enormously to the development and progression of chronic heart failure. Despite the identification of efficacious pharmacological regimens and introduction of mechanical interventions, chronic heart failure remains among the leading causes of mortality worldwide. To introduce novel therapeutic strategies that modulate the inflammatory response in the context of the failing heart, it is of prime importance to determine the contributions of TNF-α, IL-6, IL-1, and IL-18 in mediating cardiac adaptive and maladaptive responses, as well as delineating their downstream intracellular signaling pathways and their potential therapeutic implications.
authors.affiliation: Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mona
authors.initials: M
authors.lastname: Hedayat
authors.forename: Mohammad Jafar
authors.initials: MJ
authors.lastname: Mahmoudi
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
mesh_terms: D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood*; D006333:Heart Failure / Q000276:immunology*; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D020382:Interleukin-18 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D032383:Myocytes, Cardiac / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha
references.citation: Cell. 1998 Oct 2;95(1):29-39
references.pmid: 9778245
references.citation: J Cell Physiol. 2008 Jun;215(3):697-707
references.pmid: 18064631
references.citation: Am J Cardiol. 2002 Nov 15;90(10):1118-22
references.pmid: 12423714
references.citation: Eur J Immunol. 2000 Oct;30(10):3057-60
references.pmid: 11069090
references.citation: Circulation. 1998 Jul 14;98(2):149-56
references.pmid: 9679721
references.citation: Cell. 1996 Nov 15;87(4):619-28
references.pmid: 8929531
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H176-83
references.pmid: 16473963
references.citation: J Immunol. 1992 Jun 15;148(12):4066-71
references.pmid: 1602143
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12333-8
references.pmid: 12237475
references.citation: Cardiovasc Res. 2002 Mar;53(4):902-10
references.pmid: 11922900
references.citation: Am J Physiol. 1996 Apr;270(4 Pt 2):H1231-9
references.pmid: 8967361
references.citation: Cell. 1999 Apr 16;97(2):189-98
references.pmid: 10219240
references.citation: J Biol Chem. 1996 Apr 19;271(16):9535-45
references.pmid: 8621626
references.citation: J Exp Med. 1996 Mar 1;183(3):949-58
references.pmid: 8642298
references.citation: J Biol Chem. 1998 Apr 17;273(16):9703-10
references.pmid: 9545305
references.citation: J Biol Chem. 2002 Sep 20;277(38):34679-91
references.pmid: 12105209
references.citation: Am J Physiol Heart Circ Physiol. 2002 Mar;282(3):H983-9
references.pmid: 11834496
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12746-51
references.pmid: 11070088
references.citation: Am J Physiol. 1996 Oct;271(4 Pt 2):H1449-55
references.pmid: 8897939
references.citation: Cell. 1995 Jul 28;82(2):241-50
references.pmid: 7543024
references.citation: Cytokine. 1992 Sep;4(5):340-6
references.pmid: 1420994
references.citation: Circulation. 2001 Jan 30;103(4):555-61
references.pmid: 11157722
references.citation: Circulation. 2003 Aug 26;108(8):1002-8
references.pmid: 12912811
references.citation: Biochem Biophys Res Commun. 2007 Mar 9;354(2):552-8
references.pmid: 17250807
references.citation: Lupus. 2005;14(9):646-51
references.pmid: 16218459
references.citation: Heart. 2003 Jan;89(1):14-8
references.pmid: 12482782
references.citation: Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H960-9
references.pmid: 12578819
references.citation: Pharmacol Ther. 2005 Jul;107(1):131-7
references.pmid: 15963355
references.citation: Cardiovasc Res. 2006 Feb 15;69(3):666-76
references.pmid: 16426590
references.citation: J Clin Invest. 1995 Aug;96(2):1042-52
references.pmid: 7635940
references.citation: Biochem Biophys Res Commun. 2007 Oct 12;362(1):200-205
references.pmid: 17706606
references.citation: Int J Cardiol. 2002 Sep;85(1):161-71
references.pmid: 12163221
references.citation: Biochem Biophys Res Commun. 2006 Jan 20;339(3):956-63
references.pmid: 16325763
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H743-53
references.pmid: 17416608
references.citation: Eur J Heart Fail. 2004 Oct;6(6):693-703
references.pmid: 15542404
references.citation: J Clin Invest. 1995 Aug;96(2):1093-9
references.pmid: 7635944
references.citation: Ann Thorac Surg. 1998 Feb;65(2):439-43
references.pmid: 9485242
references.citation: Lab Invest. 1996 Dec;75(6):809-18
references.pmid: 8973476
references.citation: Shock. 2002 Oct;18(4):360-6
references.pmid: 12392281
references.citation: Circ Res. 1997 Nov;81(5):664-71
references.pmid: 9351439
references.citation: Exp Cell Res. 2003 Aug 1;288(1):208-17
references.pmid: 12878172
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6668-73
references.pmid: 11381115
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):315-9
references.pmid: 10618415
references.citation: Am Heart J. 2006 Oct;152(4):712.e1-6
references.pmid: 16996843
references.citation: Basic Res Cardiol. 1992 Jan-Feb;87(1):12-8
references.pmid: 1567350
references.citation: J Clin Invest. 1992 Sep;90(3):693-8
references.pmid: 1522226
references.citation: J Mol Cell Cardiol. 1989 Jan;21(1):103-13
references.pmid: 2716064
references.citation: Biochem Biophys Res Commun. 1995 Aug 24;213(3):1002-9
references.pmid: 7654217
references.citation: Int J Cardiol. 2008 Jun 6;126(3):414-20
references.pmid: 18192036
references.citation: Cell Immunol. 1996 Nov 1;173(2):230-5
references.pmid: 8912881
references.citation: Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H76-85
references.pmid: 19429811
references.citation: Cytokine. 2005 Feb 21;29(4):159-68
references.pmid: 15652448
references.citation: Br J Pharmacol. 2008 Mar;153 Suppl 1:S414-27
references.pmid: 18246092
references.citation: J Immunol. 2001 Sep 1;167(5):2879-86
references.pmid: 11509635
references.citation: Circulation. 1997 Mar 4;95(5):1247-52
references.pmid: 9054856
references.citation: Circulation. 2008 May 13;117(19):2544-65
references.pmid: 18391114
references.citation: Biochim Biophys Acta. 2007 Jan;1772(1):5-14
references.pmid: 17045464
references.citation: Int Rev Immunol. 1998;16(5-6):457-99
references.pmid: 9646173
references.citation: Circulation. 2008 May 20;117(20):2670-83
references.pmid: 18474815
references.citation: Mol Cell Biol. 1998 Jun;18(6):3518-26
references.pmid: 9584192
references.citation: Circ Res. 1999 Aug 6;85(3):272-9
references.pmid: 10436170
references.citation: Proc Natl Acad Sci U S A. 1995 May 23;92(11):4862-6
references.pmid: 7539136
references.citation: Circulation. 1993 Nov;88(5 Pt 2):II387-94
references.pmid: 8222183
references.citation: Adv Immunol. 2008;99:95-114
references.pmid: 19117533
references.citation: J Immunol. 2003 May 1;170(9):4731-7
references.pmid: 12707353
references.citation: J Cardiovasc Pharmacol. 2005 Apr;45(4):301-9
references.pmid: 15772517
references.citation: Circulation. 2002 May 7;105(18):2192-7
references.pmid: 11994254
references.citation: Circulation. 2003 Aug 5;108(5):598-604
references.pmid: 12874189
references.citation: Circulation. 2001 Sep 18;104(12 Suppl 1):I308-I3
references.pmid: 11568074
references.citation: Nature. 1995 Nov 2;378(6552):88-91
references.pmid: 7477296
references.citation: Am J Physiol. 1998 Jul;275(1):H250-8
references.pmid: 9688921
references.citation: Br J Pharmacol. 1995 Jan;114(1):27-34
references.pmid: 7536096
references.citation: J Cell Biol. 1997 Oct 6;139(1):115-27
references.pmid: 9314533
references.citation: Circulation. 2009 Mar 17;119(10):1386-97
references.pmid: 19255345
references.citation: Basic Res Cardiol. 2007 Jan;102(1):63-72
references.pmid: 16817025
references.citation: Cardiovasc Res. 2003 Jan;57(1):20-7
references.pmid: 12504810
references.citation: Science. 1995 Mar 31;267(5206):1990-4
references.pmid: 7701321
references.citation: Cardiovasc Pathol. 2005 Mar-Apr;14(2):49-60
references.pmid: 15780796
references.citation: J Mol Cell Cardiol. 1996 Aug;28(8):1631-9
references.pmid: 8877773
references.citation: Curr Opin Cardiol. 2008 May;23(3):254-60
references.pmid: 18382215
references.citation: Congest Heart Fail. 2006 Nov-Dec;12(6):324-8
references.pmid: 17170586
references.citation: Circulation. 2001 Jan 16;103(2):220-5
references.pmid: 11208680
references.citation: J Immunol. 1998 Sep 1;161(5):2217-22
references.pmid: 9725214
references.citation: Circulation. 1998 Jul 28;98(4):346-52
references.pmid: 9711940
references.citation: Circ Res. 1995 Sep;77(3):494-502
references.pmid: 7543826
references.citation: Am J Physiol. 1998 Sep;275(3):H1016-23
references.pmid: 9724308
references.citation: Circ Res. 2004 Dec 10;95(12):1140-53
references.pmid: 15591236
references.citation: JAMA. 2003 Jan 8;289(2):194-202
references.pmid: 12517230
references.citation: J Mol Cell Cardiol. 2001 Nov;33(11):1929-36
references.pmid: 11708838
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12929-34
references.pmid: 14566054
references.citation: Circ Res. 1990 Jun;66(6):1561-75
references.pmid: 2160870
references.citation: J Biol Chem. 1997 Feb 28;272(9):5828-32
references.pmid: 9038198
references.citation: Ann Rheum Dis. 2000 Nov;59 Suppl 1:i90-3
references.pmid: 11053097
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 May;292(5):R1900-6
references.pmid: 17234961
references.citation: Cytokine. 1995 Apr;7(3):251-9
references.pmid: 7640345
references.citation: Circ Res. 2002 Nov 29;91(11):988-98
references.pmid: 12456484
references.citation: Gastroenterology. 2001 Nov;121(5):1145-57
references.pmid: 11677207
references.citation: J Am Coll Cardiol. 2000 Apr;35(5):1338-46
references.pmid: 10758978
references.citation: Zhonghua Yi Xue Za Zhi. 2004 Apr 2;84(7):548-53
references.pmid: 15144587
references.citation: Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1635-44
references.pmid: 11009450
references.citation: Circulation. 2002 Dec 10;106(24):3068-72
references.pmid: 12473553
references.citation: Circ Res. 1997 Oct;81(4):627-35
references.pmid: 9314845
references.citation: Cardiovasc Res. 2003 Jul 1;59(1):122-31
references.pmid: 12829183
references.citation: Circulation. 2001 Aug 14;104(7):826-31
references.pmid: 11502710
references.citation: Circ Res. 2002 Feb 8;90(2):128-34
references.pmid: 11834704
references.citation: J Biol Chem. 2003 May 2;278(18):16304-9
references.pmid: 12595539
references.citation: J Immunol. 1993 Aug 1;151(3):1682-90
references.pmid: 8335952
references.citation: Cell. 1995 Jan 27;80(2):285-91
references.pmid: 7834748
references.citation: Cardiovasc Res. 2006 Jan;69(1):164-77
references.pmid: 16219301
references.citation: EMBO J. 2000 Dec 1;19(23):6341-50
references.pmid: 11101507
references.citation: Circulation. 1998 Apr 14;97(14):1392-400
references.pmid: 9577951
references.citation: Autoimmunity. 2004 Mar;37(2):131-45
references.pmid: 15293883
references.citation: Nihon Geka Gakkai Zasshi. 1998 Aug;99(8):485-9
references.pmid: 9789282
references.citation: Biochem Biophys Res Commun. 1992 Apr 30;184(2):1056-9
references.pmid: 1374234
references.citation: Proc Natl Acad Sci U S A. 1990 Jun;87(11):4275-9
references.pmid: 2349236
references.citation: Circ Res. 1999 Jan 8-22;84(1):21-33
references.pmid: 9915771
references.citation: Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1303-11
references.pmid: 15317679
references.citation: Cardiovasc Res. 2000 Sep;47(4):797-805
references.pmid: 10974228
references.citation: J Mol Cell Cardiol. 2002 May;34(5):583-96
references.pmid: 12056861
references.citation: Cardiovasc Res. 1999 Mar;41(3):514-23
references.pmid: 10435023
references.citation: Circ Res. 1995 Sep;77(3):486-93
references.pmid: 7543825
references.citation: Proc Natl Acad Sci U S A. 1990 Jul;87(13):5026-30
references.pmid: 2367521
references.citation: Circulation. 2004 Apr 6;109(13):1594-602
references.pmid: 15023878
references.citation: Circ Res. 2002 Dec 13;91(12):1119-26
references.pmid: 12480812
references.citation: J Am Coll Cardiol. 1996 Jul;28(1):247-52
references.pmid: 8752821
references.citation: Life Sci. 2006 Apr 25;78(22):2633-42
references.pmid: 16310223
references.citation: Presse Med. 2004 Feb 28;33(4):256-61; discussion 269
references.pmid: 15029017
references.citation: J Immunol. 1988 Nov 1;141(9):3106-10
references.pmid: 3262680
references.citation: J Mol Cell Cardiol. 1988 Mar;20(3):267-76
references.pmid: 3398057
references.citation: Biochem J. 1998 Sep 1;334 ( Pt 2):297-314
references.pmid: 9716487
references.citation: J Mol Cell Cardiol. 2005 Sep;39(3):545-51
references.pmid: 15890357
references.citation: J Card Fail. 2001 Dec;7(4):355-64
references.pmid: 11782860
references.citation: Eur J Heart Fail. 2009 Feb;11(2):119-29
references.pmid: 19168509
references.citation: Shock. 2002 May;17(5):345-53
references.pmid: 12022752
references.citation: Heart Fail Rev. 2001 Mar;6(2):119-27
references.pmid: 11309530
references.citation: Circulation. 2007 Mar 20;115(11):1398-407
references.pmid: 17353445
references.citation: Circ Res. 2003 Apr 4;92(6):589-91
references.pmid: 12637370
references.citation: Circulation. 2006 Nov 28;114(22):2364-73
references.pmid: 17101849
references.citation: Lancet. 2008 Jan 19;371(9608):228-36
references.pmid: 18207018
references.citation: Circulation. 1998 Apr 14;97(14):1382-91
references.pmid: 9577950
references.citation: Circulation. 2004 Feb 17;109(6):750-5
references.pmid: 14970111
references.citation: J Clin Invest. 2007 Sep;117(9):2692-701
references.pmid: 17694177
references.citation: Circ Res. 1997 Oct;81(4):493-503
references.pmid: 9314830
references.citation: Eur Surg Res. 2001 Sep-Dec;33(5-6):383-7
references.pmid: 11805400
references.citation: Basic Clin Pharmacol Toxicol. 2006 Dec;99(6):391-7
references.pmid: 17169118
references.citation: Circulation. 1994 Jul;90(1):375-83
references.pmid: 7517798
references.citation: Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2421-32
references.pmid: 16973967
references.citation: J Card Fail. 2008 Feb;14(1):61-74
references.pmid: 18226775
references.citation: Can J Cardiol. 1996 Dec;12(12):1259-67
references.pmid: 8987966
references.citation: J Biol Chem. 2001 Oct 5;276(40):37069-75
references.pmid: 11477102
references.citation: Am J Physiol Heart Circ Physiol. 2002 Apr;282(4):H1288-95
references.pmid: 11893563
references.citation: Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H708-14
references.pmid: 15821032
references.citation: Heart Fail Rev. 2004 Jan;9(1):43-51
references.pmid: 14739767
references.citation: Circulation. 2003 Jul 1;107(25):3133-40
references.pmid: 12796126
references.citation: Experientia. 1989 Jun 15;45(6):526-35
references.pmid: 2472287
references.citation: Heart Fail Rev. 2006 Mar;11(1):83-92
references.pmid: 16819581
references.citation: J Biol Chem. 1994 Nov 4;269(44):27580-8
references.pmid: 7525557
references.citation: Am J Physiol. 1999 Jan;276(1):R265-76
references.pmid: 9887205
references.citation: Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H650-7
references.pmid: 12124212
references.citation: Annu Rev Pathol. 2006;1:297-329
references.pmid: 18039117
references.citation: J Mol Cell Cardiol. 1999 Nov;31(11):1997-2006
references.pmid: 10591026
references.citation: Res Commun Mol Pathol Pharmacol. 1996 Aug;93(2):149-62
references.pmid: 8884986
references.citation: Acta Pharmacol Sin. 2004 Sep;25(9):1157-64
references.pmid: 15339391
references.citation: Circ Res. 2000 Jun 23;86(12):1259-65
references.pmid: 10864917
references.citation: J Immunol. 1999 Jan 15;162(2):1096-100
references.pmid: 9916738
references.citation: Basic Res Cardiol. 2004 Jan;99(1):18-28
references.pmid: 14685702
references.citation: Chin Med J (Engl). 2004 Aug;117(8):1135-42
references.pmid: 15361284
references.citation: Curr Med Chem. 2006;13(16):1877-93
references.pmid: 16842199
references.citation: Br J Pharmacol. 1987 Nov;92(3):639-46
references.pmid: 3322462
references.citation: Baillieres Best Pract Res Clin Haematol. 1999 Sep;12(3):343-59
references.pmid: 10856974
references.citation: J Mol Cell Cardiol. 1998 Oct;30(10):2003-12
references.pmid: 9799654
references.citation: Lab Invest. 1979 Mar;40(3):364-72
references.pmid: 423529
references.citation: Cytokine. 2003 Jun 7;22(5):142-8
references.pmid: 12842762
references.citation: J Clin Invest. 1998 Feb 1;101(3):711-21
references.pmid: 9449707
references.citation: Beijing Da Xue Xue Bao Yi Xue Ban. 2007 Dec 18;39(6):570-5
references.pmid: 18087543
references.citation: Science. 1988 Nov 11;242(4880):941-4
references.pmid: 3263703
references.citation: Basic Res Cardiol. 2007 Jul;102(4):279-97
references.pmid: 17530315
references.citation: J Mol Cell Cardiol. 1994 Feb;26(2):229-42
references.pmid: 8006984
references.citation: Perfusion. 2008 Jul;23(4):237-42
references.pmid: 19181757
references.citation: Ann N Y Acad Sci. 1999 Jun 30;874:69-82
references.pmid: 10415522
references.citation: Curr Drug Targets. 2008 Apr;9(4):325-44
references.pmid: 18393826
references.citation: J Biol Chem. 1995 May 5;270(18):10915-22
references.pmid: 7738033
references.citation: J Immunol. 1996 Nov 1;157(9):3967-73
references.pmid: 8892629
references.citation: J Biol Chem. 2004 Sep 17;279(38):39513-9
references.pmid: 15269222
references.citation: Circulation. 2001 Sep 18;104(12):1424-9
references.pmid: 11560860
references.citation: EMBO J. 2000 Jun 1;19(11):2537-48
references.pmid: 10835352
references.citation: J Mol Cell Cardiol. 2002 Oct;34(10):1309-16
references.pmid: 12392991
references.citation: Mol Cell Biochem. 1996 Jul-Aug;160-161:217-24
references.pmid: 8901476
references.citation: J Mol Cell Cardiol. 1995 Oct;27(10):2091-9
references.pmid: 8576926
references.citation: Pflugers Arch. 2002 Nov;445(2):246-56
references.pmid: 12457245
references.citation: Annu Rev Immunol. 2001;19:423-74
references.pmid: 11244043
references.citation: Cardiovasc Res. 2008 Aug 1;79(3):360-76
references.pmid: 18487233
references.citation: J Biol Chem. 2005 Feb 11;280(6):4553-67
references.pmid: 15574430
references.citation: J Clin Invest. 1995 Jun;95(6):2555-64
references.pmid: 7769098
references.citation: Shock. 2005 Dec;24(6):564-70
references.pmid: 16317388
references.citation: Am J Cardiol. 2005 Jun 6;95(11A):3C-8C; discussion 38C-40C
references.pmid: 15925558
references.citation: Cardiovasc Res. 2007 Oct 1;76(1):81-90
references.pmid: 17612514
references.citation: Basic Res Cardiol. 2004 Sep;99(5):328-37
references.pmid: 15309410
references.citation: Arthritis Res. 2002;4 Suppl 3:S233-42
references.pmid: 12110143
references.citation: J Clin Invest. 1995 Feb;95(2):677-85
references.pmid: 7532189
references.citation: Biochem Biophys Res Commun. 2004 Oct 1;322(4):1214-22
references.pmid: 15336969
references.citation: Cardiovasc Res. 2007 Aug 1;75(3):536-45
references.pmid: 17559824
references.citation: J Mol Cell Cardiol. 1998 Nov;30(11):2281-9
references.pmid: 9925365
references.citation: J Biol Chem. 2004 May 7;279(19):20221-33
references.pmid: 14960579
references.citation: Circulation. 1996 Nov 15;94(10):2626-32
references.pmid: 8921810
references.citation: Int J Exp Pathol. 2000 Feb;81(1):1-16
references.pmid: 10718860
references.citation: Circulation. 1998 Aug 25;98(8):794-9
references.pmid: 9727550
references.citation: Circulation. 2004 Apr 20;109(15):1892-7
references.pmid: 15051641
references.citation: Curr Opin Immunol. 2000 Feb;12(1):59-63
references.pmid: 10679398
references.citation: Genes Dev. 1999 Nov 15;13(22):2905-27
references.pmid: 10579998
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):793-8
references.pmid: 10639159
references.citation: Am J Physiol. 1998 Jan;274(1):H249-58
references.pmid: 9458874
references.citation: Int J Hematol. 2001 Jul;74(1):3-8
references.pmid: 11530802
references.citation: Annu Rev Immunol. 2009;27:519-50
references.pmid: 19302047
references.citation: J Biol Chem. 1997 Feb 21;272(8):4836-42
references.pmid: 9030540
references.citation: Circ Res. 1994 Aug;75(2):285-95
references.pmid: 7518362