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(Journal of Leukocyte Biology. 2002;72:790-799.)
© 2002 by Society for Leukocyte Biology

Dissociated ROS production and ceramide generation in sulfasalazine-induced cell death in Raw 264.7 cells

The Jack Bell Research Centre, Vancouver, British Columbia, Canada

Correspondence: Dr. B. Salh, Division of Gastroenterology, University of British Columbia, 100-2647 Willow Street, Vancouver, BC, V5Z 3P1, Canada. E-mail: bsalh{at}interchange.ubc.ca

Sulfasalazine (SSZ) is a drug used in inflammatory bowel disease, whose precise mechanism of action remains to be clarified. Here, we report that incubation of Raw 264.7 cells with SSZ but not salicylates [acetylsalicylic acid (ASA), 4-aminosalicylic acid (4-ASA), and 5-ASA] causes a mixed apoptotic and necrotic form of cell death. In contrast to its metabolites, sulfapyridine and 5-ASA, SSZ exposure in Raw 264.7 cells resulted in a threefold increase in ceramide generation, as well as a robust production of reactive oxygen species (ROS). However, inhibition of ceramide production by fumonisin B1 failed to attenuate cell death. Preincubation with catalase, cyclosporin A (CsA), and bongkrekic acid attenuated ROS production. When dead cells were quantified for apoptotic versus necrotic cell death, catalase and N-acetylcysteine reproducibly attenuated apoptosis, whereas CsA, in addition to reducing apoptosis, was observed to dramatically enhance necrosis. In conclusion, the cell-death response induced by SSZ in Raw 264.7 cells involves ROS in the apoptotic limb but is independent of ceramide formation.

Key Words: macrophages • apoptosis • necrosis • MAPK • PLD

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