Abstract
The initiation of an immune response to small molecules is believed to require the release of stress/danger signals that activate resident dendritic cells, presumably secondary to the formation of reactive metabolites. We hypothesized that exposure to arylhydroxylamine metabolites of dapsone and sulfamethoxazole lead to the expression/release of numerous stress signals in the skin. To test this hypothesis, we examined the effect of these metabolites on the expression of selected heat shock proteins, uric acid, cytokines, adhesion molecules, and costimulatory molecules in normal human epidermal keratinocytes (NHEKs). NHEKs showed a time-dependent up-regulation of heat shock protein 70 and translocation of heat shock protein 27 when exposed to the arylhydroxylamine metabolites. In addition, the secretion of several proinflammatory cytokines was increased upon incubation of these cells with metabolite. In contrast, the uric acid concentration was not altered. Moreover, intercellular adhesion molecule-1, CD80, and CD86 expressions did not change when NHEKs were exposed to these reactive metabolites. Our data suggest that NHEKs selectively up-regulate certain danger signals when exposed to arylhydroxylamine metabolites. These signals may subsequently activate dendritic cells and initiate an immune response within skin.
Footnotes
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This work was supported in part by National Institutes of Health Grant GM63821 (to C.K.S.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126615.
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ABBREVIATIONS: CDR, cutaneous drug reaction; SMX, sulfamethoxazole; DDS, dapsone; S-NOH, sulfamethoxazole hydroxylamine; D-NOH, dapsone hydroxylamine; APC, antigen-presenting cell; LC, Langerhans cell; Hsp, heat shock protein; ICAM-1, intercellular adhesion molecule-1; IFN-α, interferon-α; NHEK, normal human epidermal keratinocyte; KGM-2, keratinocyte growth medium; DAPI, 4,6-diamidino-2-phenylindole; IL-1β, interleukin 1β; TNF-α-tumor necrosis factor-α; IFN-γ, interferon-γ; PMA, phorbol 12-myristate 13-acetate; DMSO, dimethyl sulfoxide.
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↵1 Current affiliation: Rutgers University, Department of Pharmacology and Toxicology, Piscataway, New Jersey.
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↵2 Current affiliation: Riley Hospital for Children, Wells Center for Pediatric Research, Indianapolis, Indiana.
- Received June 2, 2007.
- Accepted August 30, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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