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TOXICOLOGY

Effect of Arylhydroxylamine Metabolites of Sulfamethoxazole and Dapsone on Stress Signal Expression in Human Keratinocytes

Division of Pharmaceutics, The University of Iowa, Iowa City, Iowa (F.D.K., P.M.V., C.K.S.); Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland (A.A.G.); and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (C.K.S.)

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.

Address correspondence to: Dr. Craig Svensson, Office of the Dean, College of Pharmacy, Nursing, and Health Sciences. Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091. E-mail: svensson{at}purdue.edu