title: In Vivo Suppression of Heat Shock Protein (HSP)27 and HSP70 Accelerates DMBA-Induced Skin Carcinogenesis by Inducing Antigenic Unresponsiveness to the Initiating Carcinogenic Chemical.
abstract: Heat shock proteins (HSPs) are constitutively expressed in murine skin. HSP27 is present in the epidermis, and HSP70 can be found in both the epidermis and dermis. The purpose of this study was to investigate the role of these proteins in cutaneous chemical carcinogenesis and to determine whether their effects on cell-mediated immune function were a contributing factor. In vivo inhibition of HSP27 and HSP70 produced a reduction in the T cell-mediated immune response to 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene in C3H/HeN mice and resulted in a state of Ag-specific tolerance. When mice were pretreated with anti-HSP27 and anti-HSP70 Abs in vivo prior to subjecting them to a standard two-stage DMBA/12-O-tetradecanoylphorbol-13-acetate cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (p < 0.05) in anti-HSP27- and HSP70-pretreated animals compared with mice pretreated with control Ab. Similar results were obtained when the data were evaluated as the cumulative number of tumors per group. Mice pretreated with HSP27 and HSP70 Abs developed more H-ras mutations and fewer DMBA-specific cytotoxic T lymphocytes. These findings indicate that in mice HSP27 and HSP70 play a key role in the induction of cell-mediated immunity to carcinogenic polyaromatic hydrocarbons. Bolstering the immune response to carcinogenic polyaromatic hydrocarbons may be an effective method for prevention of the tumors that they produce.
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and Veteran Affairs Medical Center, Birmingham, AL 35294 nabihayusuf@uabmc.edu.
authors.forename: Nabiha
authors.initials: N
authors.lastname: Yusuf
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and.
authors.forename: Tahseen H
authors.initials: TH
authors.lastname: Nasti
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and.
authors.forename: Israr
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and.
authors.forename: Sanim
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mohiuddin
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and Veteran Affairs Medical Center, Birmingham, AL 35294.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and Veteran Affairs Medical Center, Birmingham, AL 35294.
authors.forename: Laura
authors.initials: L
authors.lastname: Timares
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama, Birmingham, AL 35294; and Veteran Affairs Medical Center, Birmingham, AL 35294.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000276:immunology / Q000633:toxicity; D000818:Animals; D063646:Carcinogenesis / Q000276:immunology*; D002273:Carcinogens / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism
chemical_list: D002273:Carcinogens; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene
references.citation: Pharmacol Ther. 1992;54(1):63-128
references.pmid: 1528955
references.citation: J Exp Med. 1992 Dec 1;176(6):1693-702
references.pmid: 1460426
references.citation: J Invest Dermatol. 1993 Sep;101(3):334-8
references.pmid: 8370970
references.citation: Int J Cancer. 1993 Nov 11;55(5):760-4
references.pmid: 8244572
references.citation: Int J Cancer. 1995 Mar 3;60(5):689-93
references.pmid: 7860144
references.citation: J Immunol. 1995 Oct 1;155(7):3530-7
references.pmid: 7561049
references.citation: Biochem Biophys Res Commun. 1996 Jan 17;218(2):582-7
references.pmid: 8561799
references.citation: Eur J Cancer. 1997 May;33(6):873-7
references.pmid: 9291808
references.citation: Semin Immunol. 1997 Oct;9(5):315-22
references.pmid: 9327526
references.citation: Gynecol Oncol. 1998 Apr;69(1):14-6
references.pmid: 9570992
references.citation: Hum Pathol. 1998 Oct;29(10):1050-5
references.pmid: 9781640
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14915-9
references.pmid: 9843990
references.citation: Vaccine. 2005 Jan 11;23(8):1029-36
references.pmid: 15620476
references.citation: J Exp Med. 2005 Jan 17;201(2):173-9
references.pmid: 15657287
references.citation: Nat Rev Immunol. 2005 Apr;5(4):296-306
references.pmid: 15803149
references.citation: Anticancer Res. 2006 Mar-Apr;26(2B):1343-9
references.pmid: 16619543
references.citation: Cell Cycle. 2006 Nov;5(22):2592-601
references.pmid: 17106261
references.citation: Methods Mol Biol. 2007;380:365-76
references.pmid: 17876106
references.citation: Vaccine. 2008 Aug 19;26 Suppl 10:iii-iv
references.pmid: 18847562
references.citation: J Immunol. 2009 Jan 1;182(1):675-83
references.pmid: 19109201
references.citation: Expert Opin Biol Ther. 2009 Feb;9(2):179-86
references.pmid: 19236248
references.citation: J Immunol. 2009 Jul 15;183(2):1463-70
references.pmid: 19553527
references.citation: Rev Environ Health. 2010 Jul-Sep;25(3):255-9
references.pmid: 21038759
references.citation: Ann N Y Acad Sci. 2013 May;1284:1-5
references.pmid: 23651186
references.citation: Carcinogenesis. 2013 Jun;34(6):1181-8
references.pmid: 23563090
references.citation: Cancer Res. 2008 May 15;68(10):3924-30
references.pmid: 18483278
references.citation: J Exp Med. 2000 Feb 7;191(3):423-34
references.pmid: 10662788
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3485-90
references.pmid: 10725409
references.citation: Immunity. 2000 Mar;12(3):263-72
references.pmid: 10755613
references.citation: Int Immunol. 2000 Nov;12(11):1539-46
references.pmid: 11058573
references.citation: Mol Carcinog. 2001 Feb;30(2):111-8
references.pmid: 11241758
references.citation: Annu Rev Immunol. 2001;19:47-64
references.pmid: 11244030
references.citation: Eur J Immunol. 2001 May;31(5):1602-9
references.pmid: 11465118
references.citation: Immunity. 2001 Dec;15(6):971-83
references.pmid: 11754818
references.citation: Annu Rev Immunol. 2002;20:395-425
references.pmid: 11861608
references.citation: Hepatology. 2003 Jan;37(1):198-207
references.pmid: 12500205
references.citation: Annu Rev Immunol. 2003;21:685-711
references.pmid: 12615891
references.citation: Nat Med. 2000 Apr;6(4):435-42
references.pmid: 10742151
references.citation: J Invest Dermatol. 2003 Jul;121(1):51-64
references.pmid: 12839563
references.citation: Histol Histopathol. 2004 Jan;19(1):119-28
references.pmid: 14702179
references.citation: J Immunol Methods. 2004 Feb 1;285(1):25-40
references.pmid: 14871532
references.citation: Nat Rev Mol Cell Biol. 2004 Oct;5(10):781-91
references.pmid: 15459659
references.citation: Nature. 1984 Feb 16-22;307(5952):658-60
references.pmid: 6694757
references.citation: Nature. 1986 Jul 3-9;322(6074):78-80
references.pmid: 3014349
references.citation: Proc Natl Acad Sci U S A. 1986 Aug;83(16):6048-52
references.pmid: 3016738
references.citation: Carcinogenesis. 1987 Oct;8(10):1481-4
references.pmid: 3115617
references.citation: Cancer Res. 1987 Nov 15;47(22):6074-8
references.pmid: 3117362
references.citation: J Invest Dermatol. 1992 May;98(5):786-90
references.pmid: 1569328