Dexamethasone differentially regulates cytokine transcription and translation in macrophages responding to bacteria or okadaic acid.
Many microorganisms and microbial products induce expression of pro-inflammatory cytokines such as interleukin-1 (IL-1alpha/beta) and tumour necrosis factor-alpha (TNF-alpha) in macrophages, primarily by transcriptional activation. We show here, by using mouse macrophages in primary culture, that pre-treatment with dexamethasone inhibits bacteria-induced IL-1beta expression as mRNA and cellular pro-IL-1beta in parallel, consistent with an effect primarily on transcriptional activation. In contrast, the expression of TNF-alpha mRNA was only partly inhibited despite virtually complete inhibition of TNF-alpha protein formation. Furthermore, the selective induction of primarily cell-associated 26,000 M, pro-TNF-alpha by the protein phosphatase inhibitor okadaic acid also was partly inhibited at the mRNA level by dexamethasone, whereas additional translational inhibition appeared to be lacking. This latter finding is reminiscent of earlier findings regarding signalling to activation of cytosolic phospholipase A2, which is sensitive to dexamethasone when elicited by bacteria, but not when elicited by okadaic acid. The present results raise the possibility that the inhibitory effect of dexamethasone on TNF-alpha translation, but not on transcriptional activation, is mediated by one or more okadaic acid-sensitive protein phosphatases.
Gewert
K
K
Department of Cell and Molecular Biology, Lund University, Sweden.
Svensson
U
U
Andersson
K
K
Holst
E
E
Sundler
R
R
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D016967:Fusobacterium nucleatum / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D007375:Interleukin-1 / Q000235:genetics*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D019319:Okadaic Acid / Q000276:immunology / Q000494:pharmacology; D010462:Peptostreptococcus / Q000276:immunology; D011425:Propionibacterium acnes / Q000276:immunology; D014176:Protein Biosynthesis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D003907:Dexamethasone