sphingosine-1-phosphate and Intestinal-Diseases

Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, and the kinase that produces it have now emerged as key regulators of numerous cellular processes involved in inflammation and cancer. Here, we review the importance of S1P in colitis and colitis-associated cancer (CAC) and discuss our recent work demonstrating that S1P produced by upregulation of SphK1 during colitis and associated cancer is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. The effectiveness of the pro-drug FTY720 (known as fingolimod), approved for the treatment of multiple sclerosis, has become the gold standard for S1P-centric drugs, and will be used to illustrate the therapeutic value of modulating SphK1 and S1P receptor functions. We will discuss our recent results showing that FTY720/fingolimod administration interferes with the SphK1/S1P/S1PR1 axis and suppresses the NF-κB/IL-6/Stat3 malicious amplification loop and CAC. These preclinical studies suggest that FTY720/fingolimod may be useful in treating colon cancer in individuals with ulcerative colitis.

Topics: Animals; Chronic Disease; Humans; Intestinal Diseases; Lysophospholipids; Neoplasms; Signal Transduction; Sphingosine

It has been shown that dietary materials are involved in immune regulation in the intestine. Lipids mediate immune regulation through a complex metabolic network that produces many kinds of lipid mediators. Sphingosine-1-phosphate (S1P) is a lipid mediator that controls cell trafficking and activation. In this review, we focus on the immunological functions of S1P in the regulation of intestinal immune responses such as immunoglobulin A production and unique T cell trafficking, and its role in the development of intestinal immune diseases such as food allergies and intestinal inflammation, and also discuss the relationship between dietary materials and S1P metabolism.

Topics: Animals; Diet; Food; Food Hypersensitivity; Humans; Immunoglobulin A; Intestinal Diseases; Intestines; Lysophospholipids; Mice; Rats; Sphingosine; T-Lymphocytes

Recent research has linked sphingolipid (SL) metabolism with cystic fibrosis transmembrane conductance regulator (CFTR) activity, affecting bioactive lipid mediator sphingosine-1-phosphate (S1P). We hypothesize that loss of CFTR function in cystic fibrosis (CF) patients influenced plasma S1P levels. Total and unbound plasma S1P levels were measured in 20 lung-transplanted adult CF patients and 20 healthy controls by mass spectrometry and enzyme-linked immunosorbent assay (ELISA). S1P levels were correlated with CFTR genotype, routine laboratory parameters, lung function and pathogen colonization, and clinical symptoms. Compared to controls, CF patients showed lower unbound plasma S1P, whereas total S1P levels did not differ. A positive correlation of total and unbound S1P levels was found in healthy controls, but not in CF patients. Higher unbound S1P levels were measured in ΔF508-homozygous compared to ΔF508-heterozygous CF patients (

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Heterozygote; Homozygote; Humans; Intestinal Diseases; Lung; Lung Transplantation; Lysophospholipids; Male; Middle Aged; Sphingosine