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

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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

Fingerprint

Colitis
Monocytes
Cytokines
Interleukin-10
Interleukin-12
Inflammatory Bowel Diseases
tetomilast
Anti-Inflammatory Agents
Phosphorylation
Type 4 Cyclic Nucleotide Phosphodiesterase
Phosphodiesterase 4 Inhibitors
Serum Amyloid A Protein
Therapeutic Uses
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases
Reverse Transcriptase Polymerase Chain Reaction
Superoxides
Pharmaceutical Preparations
Chronic Obstructive Pulmonary Disease
Lipopolysaccharides

Keywords

  • Monocyte
  • PDE4 inhibitor
  • Tetomilast

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in Il-10-deficient mice. / Ichikawa, Hitoshi; Okamoto, Susumu; Kamada, Nobuhiko; Nagamoto, Hisashi; Kitazume, Mina T.; Kobayashi, Taku; Chinen, Hiroshi; Hisamatsu, Tadakazu; Hibi, Toshifumi.

In: Inflammatory Bowel Diseases, Vol. 14, No. 11, 2008, p. 1483-1490.

Research output: Contribution to journalArticle

Ichikawa, H, Okamoto, S, Kamada, N, Nagamoto, H, Kitazume, MT, 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, vol. 14, no. 11, pp. 1483-1490. https://doi.org/10.1002/ibd.20524
Ichikawa, Hitoshi ; Okamoto, Susumu ; Kamada, Nobuhiko ; Nagamoto, Hisashi ; Kitazume, Mina T. ; Kobayashi, Taku ; Chinen, Hiroshi ; Hisamatsu, Tadakazu ; Hibi, Toshifumi. / Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in Il-10-deficient mice. In: Inflammatory Bowel Diseases. 2008 ; Vol. 14, No. 11. pp. 1483-1490.
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AU - Okamoto, Susumu

AU - Kamada, Nobuhiko

AU - Nagamoto, Hisashi

AU - Kitazume, Mina T.

AU - Kobayashi, Taku

AU - Chinen, Hiroshi

AU - Hisamatsu, Tadakazu

AU - Hibi, Toshifumi

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