Abstract
Alcohol has been reported to be a risk factor in psoriasis mainly based on the observation that there is a higher prevalence of alcohol abuse in individuals with psoriasis. The mechanism by which alcohol affects this disease is still elusive. So far there are no reports describing the effects of metabolites relevant to alcohol metabolism on the growth of human keratinocytes. In the present study we examined the effects of ethanol and acetone, which exceeds its normal endogenous level in the blood of heavy drinkers, on the proliferation of HaCaT keratinocytes. HaCaT cells were incubated for 30 min in the presence of various concentrations of ethanol (2.14 mM–1.71 M) and acetone (1.7 mM–1.36 M). The numbers of viable and proliferating cells were determined at different times after ethanol and acetone treatment. The effects of ethanol and acetone on the mRNA levels of genes characteristic for proliferating keratinocytes such as α5 integrin, keratinocyte growth factor receptor and cyclin D1 were studied by reverse-transcriptase polymerase chain reaction. Both ethanol and acetone induced proliferation of HaCaT cells. The maximum increase in the number of viable cells and the maximum proliferative response was observed with 4.28 mM ethanol and 13.6 mM acetone. The α5 integrin, keratinocyte growth factor receptor and cyclin D1 mRNA levels were higher compared to the controls as early as 2 h after ethanol and 30 min after acetone treatment of the cells. The stimulatory effect of ethanol and acetone on human keratinocytes may be one of the reasons why psoriasis can be precipitated by alcohol misuse.
Similar content being viewed by others
References
Andreadis ST, Hamoen KE, Yarmush ML, Morgan JR (2001) Keratinocyte growth factor induces hyperproliferation and delays differentiation in a skin equivalent model system. FASEB J 15:898–906
Baker RC, Jerrells TR (1993) Recent developments in alcoholism: immunological aspects. Recent Dev Alcohol 11:249–271
Barker JN, Sarma V, Mitra RS, Dixit VM, Nickoloff BJ (1990) Marked synergism between tumor necrosis factor-alpha and interferon-gamma in regulation of keratinocyte-derived adhesion molecules and chemotactic factors. J Clin Invest 85:605–608
Bata-Csorgo Z, Hammerberg C, Voorhees JJ, Cooper KD (1993) Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis. J Exp Med 178:1271–1281
Bata-Csorgo Z, Hammerberg C, Voorhees J, Cooper KD (1995) Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes. J Clin Invest 95:317–327
Bata-Csorgo Z, Cooper KD, Kang BK, Voorhees JJ, Hammerberg C (1996) Differential expression suggesting differential functions of D-type cyclins in normal human keratinocytes (abstract). J Invest Dermatol 106:828
Bata-Csorgo Z, Cooper KD, Ting KM, Voorhees JJ, Hammerberg C (1998) Fibronectin and alpha5 integrin regulate keratinocyte cell cycling. A mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis. J Clin Invest 101:1509–1518
Braden GL, Strayhorn CH, Germain MJ, Mulhern JG, Skutches CL (1993) Increased osmolal gap in alcoholic acidosis. Arch Intern Med 153:2377–2380
Bruch-Gerharz D, Fehsel K, Suschek C, Michel G, Ruzicka T, Kolb Bachofen V (1996) A proinflammatory activity of interleukin 8 in human skin: expression of the inducible nitric oxide synthase in psoriatic lesions and cultured keratinocytes (abstract). J Exp Med 184:2007–2012
Camp RDR (1998) Psoriasis. In: Champion RH, Burton JL, Burns DA, Breathnach SM (eds) Textbook of dermatology. Blackwell Science, Oxford, pp 1589–1649
Churchill JE, Ashley DL, Kaye WE (2001) Recent chemical exposures and blood volatile organic compound levels in a large population-based sample. Arch Environ Health 56:157–166
Cluette JE, Mulligan JJ, Noring R, Doyle K, Hojnacki J (1984) Ethanol enhances de novo synthesis of high density lipoprotein cholesterol. Proc Soc Exp Biol Med 176:508–511
de Boer OJ, Wakelkamp IM, Pals ST, Claessen N, Bos JD, Das PK (1994) Increased expression of adhesion receptors in both lesional and non-lesional psoriatic skin. Arch Dermatol Res 286:304–311
Denda M, Brown BE, Elias PM, Feingold KR (1997) Epidermal injury stimulates prenylation in the epidermis of hairless mice. Arch Dermatol Res 289:104–110
Diamond I, Wrubel B, Estrin W, Gordon A (1987) Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients. Proc Natl Acad Sci U S A 84:1413–1416
Farkas A, Kemeny L, Szony BJ, Bata-Csorgo ZZ, Pivarcsi A, Kiss M, Szell M, Koreck A, Dobozy A (2001) Dithranol upregulates IL-10 receptors on the cultured human keratinocyte cell line HaCaT. Inflamm Res 50:44–49
Field FJ, Boydstun JS, LaBrecque DR (1985) Effect of chronic ethanol ingestion on hepatic and intestinal acyl coenzyme a: cholesterol acyltransferase and 3-hydroxy-3-methylglutaryl coenzyme a reductase in the rat. Hepatology 5:133–138
Finch PW, Rubin JS, Miki T, Ron D, Aaronson SA (1989) Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 245:752–755
Garach-Jehoshua O, Ravid A, Liberman UA, Koren R (1999) 1,25-Dihydroxyvitamin D3 increases the growth-promoting activity of autocrine epidermal growth factor receptor ligands in keratinocytes. Endocrinology 140:713–721
Giannelli G, Savoia P, Schiraldi O, Lospalluti M, De Luca M, Marchisio PC, Quaranta V (1994) Psoriatic lesions in patients with chronic liver disease are distinct from psoriasis vulgaris lesions, as judged on basis of integrin adhesion receptors. Hepatology 20:56–65
Gray N, Detivaud L, Doerig C, Meijer L (1999) ATP-site directed inhibitors of cyclin-dependent kinases. Curr Med Chem 6:859–875
Gupta MA, Schork NJ, Gupta AK, Ellis CN (1993) Alcohol intake and treatment responsiveness of psoriasis: a prospective study. J Am Acad Dermatol 28:730–732
Higgins EM, du Vivier A (1992) Alcohol and the skin. Alcohol Alcohol 27:595–602
Higgins EM, du Vivier AW (1994a) Alcohol abuse and treatment resistance in skin disease. J Am Acad Dermatol 30:1048
Higgins EM, du Vivier AW (1994b) Cutaneous disease and alcohol misuse. Br Med Bull 50:85–98
Higgins EM, Peters TJ, du Vivier AW (1993) Smoking, drinking and psoriasis. Br J Dermatol 129:749–750
Hoffman PL, Tabakoff B (1990) Ethanol and guanine nucleotide binding proteins: a selective interaction. FASEB J 4:2612–2622
Hoffman PL, Moses F, Tabakoff B (1989) Selective inhibition by ethanol of glutamate-stimulated cyclic GMP production in primary cultures of cerebellar granule cells. Neuropharmacology 28:1239–1243
Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25
Iffland R, Balling MP, Borsch G, Herold C, Kaschade W, Loffler T, Schmidtmann U, Stettner J (1994) Evaluation of an increased blood level of GGT, CDT, methanol, acetone and isopropanol in alcohol intoxicated automobile drivers. Alcoholism indicators instead of medical-psychological examination. Blutalkohol 31:273–314
Inohara S, Kitano Y (1994) Immunohistochemical detection of cyclin D and cyclin A in human hyperproliferative epidermis. Arch Dermatol Res 286:504–506
Kemeny L, Kenderessy AS, Ocsovszky I, Michel G, Ruzicka T, Dobozy A (1995) Interleukin-8 induces HLA-DR expression on cultured human keratinocytes via specific receptors. Int Arch Allergy Immunol 106:351–356
Kharbanda S, Nakamura T, Kufe D (1993) Induction of the c-jun proto-oncogene by a protein kinase C-dependent mechanism during exposure of human epidermal keratinocytes to ethanol. Biochem Pharmacol 45:675–681
Lehmann B (1997) HaCaT cell line as a model system for vitamin D3 metabolism in human skin. J Invest Dermatol 108:78–82
Luthin GR, Tabakoff B (1984) Activation of adenylate cyclase by alcohols requires the nucleotide-binding protein. J Pharmacol Exp Ther 228:579–587
Marchese C, Rubin J, Ron D, Faggioni A, Torrisi MR, Messina A, Frati L, Aaronson SA (1990) Human keratinocyte growth factor activity on proliferation and differentiation of human keratinocytes: differentiation response distinguishes KGF from EGF family. J Cell Physiol 144:326–332
Maruyama S, Murawaki Y, Hirayama C (1986) Effects of chronic ethanol administration on hepatic cholesterol and bile acid synthesis in relation to serum high density lipoprotein cholesterol in rats. Res Commun Chem Pathol Pharmacol 53:3–21
Mate JL, Ariza A, Roca X, Lopez D, Ferrandiz C, Perez-Piteira J, Navas-Palacios JJ (1998) expression patterns of cyclins D1 and E in condyloma acuminatum in comparison with psoriatic proliferative lesions. J Pathol 184:83–88
Meijer L, Leclerc S, Leost M (1999) Properties and potential-applications of chemical inhibitors of cyclin-dependent kinases. Pharmacol Ther 82:279–284
Mezey E (1985) Metabolic effects of alcohol. Fed Proc 44:134–138
Miki T, Fleming TP, Bottaro DP, Rubin JS, Ron D, Aaronson SA (1991) Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. Science 251:72–75
Miki T, Bottaro DP, Fleming TP, Smith CL, Burgess WH, Chan AM, Aaronson SA (1992) Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci U S A 89:246–250
Monk BE, Neill SM (1986) Alcohol consumption and psoriasis. Dermatologica 173:57–60
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Nagy LE, Diamond I, Collier K, Lopez L, Ullman B, Gordon AS (1989) Adenosine is required for ethanol-induced heterologous desensitization. Mol Pharmacol 36:744–748
Ockenfels HM, Nussbaum G, Schultewolter T, Burger PM, Goos M (1995) Cyclosporin A, FK506 and dithranol after tyrosine-specific protein phosphorylation in HaCaT keratinocytes. Arch Dermatol Res 287:304–309
Ockenfels HM, Schultewolter T, Ockenfels G, Funk R, Goos M (1998) The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. Br J Dermatol 139:390–395
Paramio JM, Lain S, Segrelles C, Lane EB, Jorcano JL (1998) Differential expression and functionally co-operative roles for the retinoblastoma family of proteins in epidermal differentiation. Oncogene 17:949–957
Paramio JM, Casanova ML, Segrelles C, Mittnacht S, Lane EB, Jorcano JL (1999) Modulation of cell proliferation by cytokeratins K10 and K16. Mol Cell Biol 19:3086–3094
Pellegrini G, De Luca M, Orecchia G, Balzac F, Cremona O, Savoia P, Cancedda R, Marchisio PC (1992) Expression, topography, and function of integrin receptors are severely altered in keratinocytes from involved and uninvolved psoriatic skin. J Clin Invest 89:1783–1795
Pines J (1995) Cyclins and cyclin-dependent kinases: theme and variations. Adv Cancer Res 66:181–212
Pivarcsi A, Szell M, Kemeny L, Dobozy A, Bata-Csorgo Z (2001) Serum factors regulate the expression of the proliferation-related genes alpha5 integrin and keratin 1, but not keratin 10, in HaCaT keratinocytes. Arch Dermatol Res 293:206–213
Prinz JC, Gross B, Vollmer S, Trommler P, Strobel I, Meurer M, Plewig G (1994) T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products. Eur J Immunol 24:593–598
Proksch E (1992) Regulation of the epidermal permeability barrier by lipids and hyperproliferation (in German). Hautarzt 43:331–338
Proksch E, Feingold KR, Man MQ, Elias PM (1991) Barrier function regulates epidermal DNA synthesis. J Clin Invest 87:1668–1673
Pronko PS, Velichko MG, Moroz AR, Rubanovich NN (1997) Low-molecular-weight metabolites relevant to ethanol metabolism: correlation with alcohol withdrawal severity and utility for identification of alcoholics. Alcohol Alcohol 32:761–768
Rabe CS, Giri PR, Hoffman PL, Tabakoff B (1990) Effect of ethanol on cyclic AMP levels in intact PC12 cells. Biochem Pharmacol 40:565–571
Robles AI, Larcher F, Whalin RB, Murillas R, Richie E, Gimenez-Conti IB, Jorcano JL, Conti CJ (1996) Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia. Proc Natl Acad Sci U S A 93:7634–7638
Ryle CM, Breitkreutz D, Stark HJ, Leigh IM, Steinert PM, Roop D, Fusenig NE (1989) Density-dependent modulation of synthesis of keratins 1 and 10 in the human keratinocyte line HACAT and in ras-transfected tumorigenic clones. Differentiation 40:42–54
Schmid P, Cox D, McMaster GK, Itin P (1993) In situ hybridization analysis of cytokine, proto-oncogene, and tumor suppressor gene expression in psoriasis. Arch Dermatol Res 285:334–340
Schwartz MA (1993) Signaling by integrins: implications for tumorigenesis. Cancer Res 53:1503–1506
Schwartz MA, Ingber DE (1994) Integrating with integrins. Mol Biol Cell 5:389–393
Sherr CJ (1993) Mammalian G1 cyclins. Cell 73:1059–1065
Vincenti GE, Blunden SM (1987) Psoriasis and alcohol abuse. J R Army Med Corps 133:77–78
Voorhees JJ (1982) "Psoriasis as a possible defect of the adenyl cyclase-cyclic AMP Cascade" by Voorhees and Duell, October 1971. Commentary: Cyclic adenosine monophosphate regulation of normal and psoriatic epidermis. Arch Dermatol 118:862–874
Watt FM, Hertle MD (1994) Keratinocyte integrins. In: Leigh I, Lane B, Watt F (eds) The keratinocyte handbook. Cambridge University Press, Cambridge, pp 153–164
Williams ML (1992) Epidermal lipids and scaling diseases of the skin. Semin Dermatol 11:169–175
Wolf R, Wolf D, Ruocco V (1999) Alcohol intake and psoriasis. Clin Dermatol 17:423–430
Acknowledgements
This work was supported by the following grants: OTKA T030749, ETT 142/2001, OTKA T032494, OTKA T032496 and AKP 2000-151 3.2 and Márta Széll was supported by the János Bolyai Foundation of the Hungarian Academy of Sciences.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Farkas, Á., Kemény, L., Széll, M. et al. Ethanol and acetone stimulate the proliferation of HaCaT keratinocytes. Arch Dermatol Res 295, 56–62 (2003). https://doi.org/10.1007/s00403-003-0399-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-003-0399-2