title: Inhibition by interleukin-10 of inducible cyclooxygenase expression in lipopolysaccharide-stimulated monocytes: its underlying mechanism in comparison with interleukin-4.
abstract: Both interleukin-10 (IL-10) and IL-4 inhibited the prostanoid synthesis of lipopolysaccharide (LPS)-stimulated human monocytes, and their inhibition was shown to be based on a common mechanism to suppress the gene expression of inducible cyclooxygenase (COX). COX has been shown to exist in at least two distinct isoforms, designated COX-1 and COX-2, and their gene expressions exhibit different profiles. At both the protein and mRNA levels, the expression of COX-1 was constitutive and was not modulated by treatments with LPS, IL-10, or IL-4. In contrast, the expression of COX-2 was observed only after stimulation with LPS. IL-10 and IL-4 significantly inhibited LPS-induced COX-2 expression. Kinetic studies showed that they inhibited COX-2 mRNA expression within 1 hour after stimulation and that maximal inhibition was consistently observed at 5 hours. Moreover, the addition of cycloheximide (CHX) to LPS-stimulated monocytes resulted in a superinduction of COX-2 mRNA, whereas CHX almost abrogated the abilities of IL-10 and IL-4 to inhibit this gene expression. Experiments with actinomycin D showed that both cytokines accelerated the degradation of COX-2 mRNA. Furthermore, nuclear run-on experiments showed that both cytokines modestly inhibited LPS-induced COX-2 gene transcription. Thus, both cytokines seemed to regulate the COX-related pathway in a similar manner, although their receptor systems did not show any structural similarities. Considering recent findings showing that the drugs that exhibit a selective effect on COX-2 may be more preferable in inflammatory conditions, such biologic activities of IL-10 and IL-4 described above may offer useful tools in controlling inflammatory disorders in the future.
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Niiro
authors.forename: T
authors.initials: T
authors.lastname: Otsuka
authors.forename: T
authors.initials: T
authors.lastname: Tanabe
authors.forename: S
authors.initials: S
authors.lastname: Hara
authors.forename: S
authors.initials: S
authors.lastname: Kuga
authors.forename: Y
authors.initials: Y
authors.lastname: Nemoto
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Nakashima
authors.forename: S
authors.initials: S
authors.lastname: Kitajima
authors.forename: M
authors.initials: M
authors.lastname: Abe
mesh_terms: D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D011451:Prostaglandin-Endoperoxide Synthases