Acid sphingomyelinase inhibition suppresses lipopolysaccharide-mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium-induced colitis in mice
| Autor: | Tsutomu Yokomatsu, Reiko Eyanagi, Akihisa Toda, Shinji Soeda, Hiroshi Shimeno, Sadao Hikishima, Akira Sakata, Takashi Ochiai, Shiroshi Shibuya |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Lipopolysaccharides
Male Pathology medicine.medical_specialty Ceramide Lipopolysaccharide Cell Survival Phosphodiesterase Inhibitors medicine.medical_treatment Immunology Biology Inflammatory bowel disease Proinflammatory cytokine Mice chemistry.chemical_compound medicine Animals Immunology and Allergy Colitis Cells Cultured Mice Inbred BALB C Tumor Necrosis Factor-alpha Macrophages Dextran Sulfate Original Articles Inflammatory Bowel Diseases medicine.disease Disease Models Animal Sphingomyelin Phosphodiesterase Cytokine chemistry Culture Media Conditioned Leukocytes Mononuclear Cytokines Inflammation Mediators Acid sphingomyelinase Sphingomyelin medicine.drug |
| Zdroj: | Immunology. 122:54-64 |
| ISSN: | 1365-2567 0019-2805 |
| DOI: | 10.1111/j.1365-2567.2007.02612.x |
| Popis: | Lipopolysaccharide (LPS) and inflammatory cytokines cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM) to produce a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related inflammatory bowel disease. We synthesized a series of difluoromethylene analogues of SM (SMAs). We report here the effects of the most potent SMase inhibitor, SMA-7, on the LPS-mediated release of tumour necrosis factor-alpha, interleukin-1beta and interleukin-6 from THP-1 macrophages and the pathology of dextran sulphate sodium (DSS)-induced colitis in mice. SMA-7 suppressed the LPS-induced cytokine release and nuclear factor-kappaB activation. LPS stimulation caused a four-fold increase in acid SMase activation, but little increase in neutral SMase activity. The presence of 10 microm SMA-7 caused acid SMase to remain at the control levels and reduced the formation of ceramide. HT-29 cells had significantly decreased cell viability when incubated with media from LPS-stimulated THP-1 macrophages. However, incubating the colon cells in media from both SMA-7 and LPS-treated macrophages caused little decrease in viability, suggesting that ceramide has a role in the LPS-stimulated signalling that releases cytotoxic factors against colon cells. Oral administration of SMA-7 to mice with 2% DSS in the drinking water, for 10 or 21 consecutive days, reduced significantly the cytokine levels in the colon and the severity of colonic injury. These findings suggest a central role for acid SMase/ceramide signalling in the pathology of DSS-induced colitis in mice, indicating a possible preventive or therapeutic role for SMase inhibitor in inflammatory bowel disease. |
| Databáze: | OpenAIRE |
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