Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in Il-10-deficient mice

Hitoshi Ichikawa, Susumu Okamoto, Nobuhiko Kamada, Hisashi Nagamoto, Mina T. Kitazume, Taku Kobayashi, Hiroshi Chinen, Tadakazu Hisamatsu, Toshifumi Hibi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Tetomilast (OPC-6535) was originally developed as a compound inhibiting superoxide production in neutrophils. Although its mechanism of action is not completely understood, phosphodiesterase type 4 inhibitory function has been postulated. The therapeutic effect of PDE4 inhibitors has been reported for chronic inflammatory disorders such as chronic obstructive pulmonary diseases. In this study we aimed to examine whether tetomilast could be a novel drug for inflammatory bowel diseases by further clarifying its antiinflammatory effects. Methods: Cytokines from human peripheral blood mononuclear cells were measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Beads Array. The transcripts were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR). Phosphorylation of transcription factors was examined by phosflow. To examine its in vivo effect, a once-daily oral dose of tetomilast was tested in murine IL-10-/- chronic colitis. Results: Tetomilast suppressed TNF-α and IL-12 but not IL-10 production from lipopolysaccharide (LPS)-stimulated human monocytes. It suppressed, TNF-α, and IFN-γ, from CD4 lymphocytes. Tetomilast suppressed cytokine production at the transcriptional level but did not alter phosphorylation of p65, ERK, p38, and STAT3. HT-89, a protein kinase A inhibitor, did not abolish the effect of tetomilast, suggesting that it was independent from the classical cAMP/PKA pathway. IL-10 was not essential to the inhibitory effect of tetomilast on and TNF-α and IL-12. Tetomilast ameliorated IL-10-/- chronic colitis with reduced clinical symptoms, serum amyloid A, and histological scores with decreased TNF-α mRNA expression. Conclusions: Tetomilast exerts its antiinflammatory effects on human monocytes and CD4 cells. Combined with in vivo data these findings support the feasibility of tetomilast as a novel drug for inflammatory bowel diseases.

Original languageEnglish
Pages (from-to)1483-1490
Number of pages8
JournalInflammatory bowel diseases
Volume14
Issue number11
DOIs
Publication statusPublished - 2008 Dec 1

Keywords

  • Monocyte
  • PDE4 inhibitor
  • Tetomilast

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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    Ichikawa, H., Okamoto, S., Kamada, N., Nagamoto, H., Kitazume, M. T., Kobayashi, T., Chinen, H., Hisamatsu, T., & Hibi, T. (2008). Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in Il-10-deficient mice. Inflammatory bowel diseases, 14(11), 1483-1490. https://doi.org/10.1002/ibd.20524