Abstract
Multiple lines of evidence suggest that macrophages have a critical role in the disease pathology of inflammatory bowel disease (IBD) by secreting inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)- 1β, IL-6 and IL-8. Therapies for IBD target one or more of these inflammatory mediators. Recent advances in drug development for IBD have involved the use of monoclonal antibodies to inhibit specific inflammatory cytokines. In particular, the anti-TNF-α antibodies, CDP571 and Infliximab have been used clinically to treat Crohns disease with some success. The inflammatory cytokines and lipopolysaccharide (LPS) cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM), to generate a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related IBD. We synthesized a series of difluoromethylene analogues of SM (SMAs). This review discusses recent data from our laboratories on the effects of the most potent SMase inhibitor, SMA-7, on the LPS-mediated releases of the cytokines from macrophages and intestinal epithelial cells and the pathology of dextran sulphate sodium (DSS)-induced colitis in mice. Our findings suggest a central role of SMase/ceramide signaling in the pathology of DSS-induced colitis in mice, indicating a possible preventive or therapeutic role for SMase inhibitor in IBD.
Keywords: Sphingomyelinase inhibitor, ceramide, nuclear factor-κB, inflammatory cytokines, macrophages, inflammatory bowel disease
Current Drug Therapy
Title: Sphingomyelinase Inhibition Suggests a Possible New Strategy for the Treatment of Inflammatory Bowel Disease
Volume: 3 Issue: 3
Author(s): Shinji Soeda, Akira Sakata, Takashi Ochiai, Kazuya Yasuda, Yukako Kuramoto, Hiroshi Shimeno, Akihisa Toda, Reiko Eyanagi, Sadao Hikishima, Tsutomu Yokomastu and Shirashi Shibuya
Affiliation:
Keywords: Sphingomyelinase inhibitor, ceramide, nuclear factor-κB, inflammatory cytokines, macrophages, inflammatory bowel disease
Abstract: Multiple lines of evidence suggest that macrophages have a critical role in the disease pathology of inflammatory bowel disease (IBD) by secreting inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)- 1β, IL-6 and IL-8. Therapies for IBD target one or more of these inflammatory mediators. Recent advances in drug development for IBD have involved the use of monoclonal antibodies to inhibit specific inflammatory cytokines. In particular, the anti-TNF-α antibodies, CDP571 and Infliximab have been used clinically to treat Crohns disease with some success. The inflammatory cytokines and lipopolysaccharide (LPS) cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM), to generate a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related IBD. We synthesized a series of difluoromethylene analogues of SM (SMAs). This review discusses recent data from our laboratories on the effects of the most potent SMase inhibitor, SMA-7, on the LPS-mediated releases of the cytokines from macrophages and intestinal epithelial cells and the pathology of dextran sulphate sodium (DSS)-induced colitis in mice. Our findings suggest a central role of SMase/ceramide signaling in the pathology of DSS-induced colitis in mice, indicating a possible preventive or therapeutic role for SMase inhibitor in IBD.
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Soeda Shinji, Sakata Akira, Ochiai Takashi, Yasuda Kazuya, Kuramoto Yukako, Shimeno Hiroshi, Toda Akihisa, Eyanagi Reiko, Hikishima Sadao, Yokomastu Tsutomu and Shibuya Shirashi, Sphingomyelinase Inhibition Suggests a Possible New Strategy for the Treatment of Inflammatory Bowel Disease, Current Drug Therapy 2008; 3 (3) . https://dx.doi.org/10.2174/157488508785747853
DOI https://dx.doi.org/10.2174/157488508785747853 |
Print ISSN 1574-8855 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3903 |
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