title: The participation of proliferative keratinocytes in the preimmune response to sensitizing agents.
abstract: The aims of this study were to investigate whether keratinocytes are capable of playing a direct preimmune role in the pathophysiology of allergic contact dermatitis (ACD) and to examine to what extent the degree of differentiation might influence this. We measured the ability of sensitizing agents to up-regulate intercellular adhesion molecule 1 (ICAM-1) expression in cultured normal human keratinocytes (NHK) and in the transformed human keratinocyte HaCaT cell line. In proliferative HaCaT cells, following a 24 h exposure, nickel compounds, para-phenylenediamine (pPD) and 1-chloro-2,4-dinitrobenzene produced a concentration-dependent up-regulation of ICAM-1 expression without reducing cell viability, while K2Cr2O7 led to ICAM-1 up-regulation at cytotoxic concentrations, and CrCl3 was without effect. In NHK, NiSO4 and pPD induced ICAM-1 expression to a significantly greater extent in proliferative cells than in differentiated cells, where involucrin expression was measured to assess the differentiation state. NiSO4- or pPD-pretreatment of proliferative HaCaT cells enhanced T-cell binding, which was abolished by neutralizing antibodies to ICAM-1 or CD18. Our investigations concerning the involvement of oxidative stress in the induction of ICAM-1 expression in response to sensitizing agents were inconclusive. The oxidizing agents FeCl3 and H2O2 up-regulated ICAM-1 expression in HaCaT cells but there was no clear relationship between the ability of agents to induce ICAM-1 expression and their ability to alter the levels of reduced glutathione. Although pPD increased interleukin-1 alpha release from NHK, this cytokine was not capable of inducing ICAM-1 expression in NHK. Tumour necrosis factor-alpha, which does induce ICAM-1 expression in NHK, was not detected in response to pPD, arguing against an autocrine pathway of ICAM-1 induction in response to pPD. In summary, we report the direct interaction of sensitizing agents with keratinocytes leading to the generation of immune signals, particularly by proliferative keratinocytes, suggesting an active role for the proliferative keratinocyte in the pathophysiology of ACD.
authors.affiliation: Department of Medicine, University of Sheffield, Northern General Hospital, U.K.
authors.forename: M C
authors.initials: MC
authors.lastname: Little
authors.forename: R A
authors.initials: RA
authors.lastname: Metcalfe
authors.forename: J W
authors.initials: JW
authors.lastname: Haycock
authors.forename: J
authors.initials: J
authors.lastname: Healy
authors.forename: D J
authors.initials: DJ
authors.lastname: Gawkrodger
authors.forename: S
authors.initials: S
authors.lastname: Mac Neil
mesh_terms: D000485:Allergens / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000276:immunology* / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D018384:Oxidative Stress; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000485:Allergens; D016207:Cytokines; D018799:Intercellular Adhesion Molecule-1