Mechanisms of dimethyl sulfoxide augmentation of IL-1 beta production.
Expression of the inflammatory cytokine IL-1beta occurs in various inflammatory diseases, and IL-1beta production is regulated at multiple levels. There are conflicting reports about the effects of antioxidants on IL-1beta production. In this study, we investigated the regulatory role of the antioxidant DMSO on LPS-stimulated IL-1beta gene expression in human PBMC and in vivo. This study demonstrated that 1% DMSO increased LPS-stimulated (50 ng/ml) IL-1beta secretion in a dose- and time-dependent manner without altering TNF or IL-6. DMSO also elevated IL-1beta secretion by PBMC in response to exogenous superoxide anions. Despite the increase in IL-1beta, there was no augmentation of NF-kappaB with the addition of DMSO. The steady state mRNA coding for IL-1beta following LPS stimulation was also increased. Cycloheximide studies demonstrated that the DMSO augmentation of IL-1beta mRNA did not require de novo protein synthesis, and studies with actinomycin D showed that DMSO did not alter the half-life of IL-1beta mRNA, suggesting that DMSO did not change the stability of IL-1beta mRNA. Experiments using a reporter vector containing the 5'-flanking region of the human IL-1beta gene revealed that DMSO augmented LPS-induced IL-1beta reporter activity. In vivo, treatment of mice with DMSO significantly increased plasma levels of IL-1beta after endotoxin challenge. These data indicate that DMSO directly increases LPS-stimulated IL-1beta protein production through the mechanisms of augmenting promoter activity and increasing mRNA levels.
Xing
Liyu
L
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Remick
Daniel G
DG
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D011498:Protein Precursors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D013481:Superoxides / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011498:Protein Precursors; D012333:RNA, Messenger; D013481:Superoxides; D003609:Dactinomycin; D003513:Cycloheximide; D004121:Dimethyl Sulfoxide