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

doi:10.1002/ibd.20524

Cited by 20 publications

(17 citation statements)

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“…18) Moreover, it has been reported that tetmilast (10 mg/kg) suppressed cytokine production in a murine chronic colitis model. 20) Therefore, we decided the dose of tetomilast as 10 mg/kg in the present study. The rabbits were divided into three groups.…”

Section: Methodsmentioning

confidence: 99%

“…16) Tetomilast also attenuates acute lung injury, 17,18) and its anti-inflammatory effects have been noted in both the liver 19) and colon. 20) In the present study, we determine whether tetomilast could be an effective treatment for PPE-induced emphysema in rabbits.…”

Section: Tetomilast Attenuates Elastase-induced Pulmonary Emphysema Tmentioning

confidence: 95%

“…20) In the present study, we determine whether tetomilast could be an effective treatment for PPE-induced emphysema in rabbits.…”

mentioning

confidence: 95%

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Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Baila

Ohno

Nagamoto

et al. 2012

Biological & Pharmaceutical Bulletin

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Tetomilast was originally identified as a potent inhibitor of superoxide production in human neutrophils, and is of interest because it may relieve oxidative stress related to chronic obstructive pulmonary disease (COPD). Our objective was to determine whether tetomilast effectively protects against the development of porcine pancreatic elastase (PPE)-induced emphysema in rabbits. Rabbits were divided into three groups (sham n 19, PPE n 19, PPE/Tetomilast n 18). The rabbits were once daily orally administered vehicle solution or tetomilast 5 d/week for 4 weeks before the PPE instillation. We compared pulmonary function, inflammatory cell infiltration, oxidative stress, and the incidences of apoptosis among the three groups. Tetomilast suppressed PPE-induced increases in the incidence of apoptosis and the production of 8-hydroxydeoxyguanosine (8-OHdG) in lung tissues. PPE-instilled rabbits treated with tetomilast showed significantly less mean linear intercept and significantly better pulmonary function than rabbits administered PPE alone. Tetomilast may inhibit the development of emphysema by attenuating pulmonary inflammation and apoptosis caused by PPE-induced oxidative stress.Key words chronic obstructive pulmonary disease; tetomilast; oxidative stress; 8-hydroxy-deoxyguanosine Pulmonary emphysema is a chronic, progressive obstructive pulmonary disease pathologically defined as "dilation of the alveolar space without desmoplasia by breakdown of alveolar walls and degradation of gas exchange." 1-6) Among the numerous factors known to play key roles in the pathogenesis of the disease are inflammation, reactive oxygen species (ROS), smoking, α 1 -antitrypsin defects and disequilibrium between elastase and anti-elastase, as well as between matrix metalloproteases (MMPs) and tissue MMP inhibitor.7-9) Airflow limitation in chronic obstructive pulmonary disease (COPD) patients results from mucosal inflammation and edema, bronchoconstriction, increased secretions in the airways and loss of elastic recoil. Phosphodiesterase 4 (PDE4) is expressed in almost all inflammatory cell types. While PDE4 inhibitors are very efficacious at inhibiting pro-inflammatory mediator release from certain cell types (e.g. neutrophils, eosinophils), 10,11) there is evidence to suggest that dual inhibition of PDE4 is additive or synergistic at suppressing the activation/ functions of other cell types, which are thought to play a role in COPD (e.g. macrophages, dendritic cells, epithelial cells, lymphocytes, airway smooth muscle cells and endothelial cells).12-15) Tetomilast (6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]-pyridine-2-carboxylic acid), a PDE4 inhibitor was initially isolated in vitro as the lead compound in a series of thiazole derivatives with inhibitory effects on superoxide production by human neutrophils. Tetomilast exerts both vasoprotectant and anti-inflammatory effects, mediated by inhibition of PDE4 and superoxide production.16) Tetomilast also attenuates acute lung injury, 17,18) and its anti-inflammatory effects have been n...

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Section: Methodsmentioning

confidence: 99%

Section: Tetomilast Attenuates Elastase-induced Pulmonary Emphysema Tmentioning

confidence: 95%

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Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Baila

Ohno

Nagamoto

et al. 2012

Biological & Pharmaceutical Bulletin

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“…29,30 Tetomilast (OPC-6535), originally developed to inhibit superoxide production, suppressed TNF-α and IL-12 but not IL-10 production from LPS-stimulated human monocytes and ameliorated chronic colitis in IL-10 −/− mice. 31 Histidine inhibited LPS-induced TNF-α and IL-6 production by mouse macrophages and dietary histidine ameliorated colitis in a IL-10 −/− mouse transfer colitis model. 32 Interestingly, amino acid profiling revealed decreased levels of plasma histidine concentration in the patients with active Crohn' s disease.…”

Section: Conditioning and Control Of Differentiation Of Innate Immunementioning

confidence: 97%

Immunological Abnormalities in the Pathogenesis of Inflammatory Bowel Disease

et al. 2012

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“…In preclinical studies it has been shown to inhibit the release of proteases, superoxide anions, and other functions attributable to activated human leukocytes [63]. Although its mode of action has not been completely understood, when tested on mouse or rat models of colitis and, in vitro, on human immune cells, it suppressed LPS-induced production of TNF-α and IL-12 in monocytes, and both TNF-α and INF-γ in CD4-positive T cells, leading to reduced colonic damages [64]. …”

Section: Pde4 Inhibitors In Preclinical Studies Of Ibdmentioning

confidence: 99%

PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue

Spadaccini

D’Alessio

Peyrin–Biroulet

et al. 2017

IJMS

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Background. In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets. The novel Phosphodiesterase 4 (PDE4) inhibitors have been recently introduced as new modulators of intracellular signals and gene transcription for the treatment of IBD. Aim. To discuss and describe the state of the art of this new class of compounds in the IBD field, with particular attention to apremilast. Methods. Published articles selected from PubMed were comprehensively reviewed, with key words including apremilast, inflammatory disease, IBD, psoriasis, psoriatic arthritis, pathogenesis, therapies, and treatment. Results. PDE4 inhibitors generate elevated intracellular levels of cyclic Adenosine Monophosphate (cAMP), that consequently down-regulate the release of pro-inflammatory cytokines in the mucosa of IBD patients. The newly developed apremilast is one of these drugs and has already been approved for the treatment of dermatologic/rheumatologic inflammatory conditions; studies in psoriasis and psoriatic arthritis have in fact demonstrated its clinical activity. However, no clinical trials have yet been published on the use of apremilast in IBD. Conclusion. In light of the similarity of pro-inflammatory signaling pathways across the gut, the skin, and joints, apremilast is likely supposed to show its efficacy also in IBD.

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

Abstract: 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.

Cited by 20 publications

References 45 publications

Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Immunological Abnormalities in the Pathogenesis of Inflammatory Bowel Disease

PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue

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