Inhibition by interleukin-10 of inducible cyclooxygenase expression in lipopolysaccharide-stimulated monocytes: Its underlying mechanism in comparison with interleukin-4

Hiroaki Niiro, Takeshi Otsuka, Tadashi Tanabe, Shuntaro Hara, Seiji Kuga, Yoshiaki Nemoto, Yosuke Tanaka, Hitoshi Nakashima, Shigetaka Kitajima, Masayoshi Abe, Yoshiyuki Niho

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88 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3736-3745
Number of pages10
JournalBlood
Volume85
Issue number12
DOIs
Publication statusPublished - Jun 15 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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