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Mechanisms of Dimethyl Sulfoxide Augmentation of IL-1 Production ¹

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602

Expression of the inflammatory cytokine IL-1 occurs in various inflammatory diseases, and IL-1 production is regulated at multiple levels. There are conflicting reports about the effects of antioxidants on IL-1 production. In this study, we investigated the regulatory role of the antioxidant DMSO on LPS-stimulated IL-1 gene expression in human PBMC and in vivo. This study demonstrated that 1% DMSO increased LPS-stimulated (50 ng/ml) IL-1 secretion in a dose- and time-dependent manner without altering TNF or IL-6. DMSO also elevated IL-1 secretion by PBMC in response to exogenous superoxide anions. Despite the increase in IL-1, there was no augmentation of NF-B with the addition of DMSO. The steady state mRNA coding for IL-1 following LPS stimulation was also increased. Cycloheximide studies demonstrated that the DMSO augmentation of IL-1 mRNA did not require de novo protein synthesis, and studies with actinomycin D showed that DMSO did not alter the half-life of IL-1 mRNA, suggesting that DMSO did not change the stability of IL-1 mRNA. Experiments using a reporter vector containing the 5'-flanking region of the human IL-1 gene revealed that DMSO augmented LPS-induced IL-1 reporter activity. In vivo, treatment of mice with DMSO significantly increased plasma levels of IL-1 after endotoxin challenge. These data indicate that DMSO directly increases LPS-stimulated IL-1 protein production through the mechanisms of augmenting promoter activity and increasing mRNA levels.