鞘氨醇激酶
炎症性肠病
鞘脂
鞘氨醇
免疫学
炎症
医学
脂质信号
免疫系统
溃疡性结肠炎
肿瘤坏死因子α
细胞因子
1-磷酸鞘氨醇
生物
受体
疾病
内科学
细胞生物学
作者
Olga Sukocheva,Elena Lukina,Eileen McGowan,Anupam Bishayee
出处
期刊:Advances in protein chemistry and structural biology
日期:2020-01-01
卷期号:: 123-158
被引量:39
标识
DOI:10.1016/bs.apcsb.2019.11.003
摘要
Morbidity of inflammatory gastrointestinal (GI) diseases continues to grow resulting in worsen quality of life and increased burden on public medical systems. Complex and heterogenous illnesses, inflammatory bowel diseases (IBDs) encompass several inflammation -associated pathologies including Crohn's disease and ulcerative colitis. IBD is often initiated by a complex interplay between host genetic and environmental factors, lifestyle and diet, and intestinal bacterial components. IBD inflammatory signature was linked to the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) signaling pathway that is currently targeted by IBD therapies. Sphingolipid signaling was identified as one of the key mediators and regulators of pro-inflammatory conditions, and, specifically, TNF-α related signaling. All GI tissues and circulating immune/blood cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinases (SphK1 and SphK2) that generate sphingosine-1-phosphate (S1P), a bioactive lipid and ligand for five G-protein coupled membrane S1P receptors (S1PRs). Numerous normal and pathogenic inflammatory responses are mediated by SphK/S1P/S1PRs signaling axis including lymphocyte trafficking and activation of cytokine signaling machinery. SphK1/S1P/S1PRs axis has recently been defined as a target for the treatment of GI diseases including IBD/colitis. Several SphK1 inhibitors and S1PRs antagonists have been developed as novel anti-inflammatory agents. In this review, we discuss the mechanisms of SphK/S1P signaling in inflammation-linked GI disorders. The potential role of SphK/S1PRs inhibitors in the prevention and treatment of IBD/colitis is critically evaluated.
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