sphingosine-1-phosphate and Colitis--Ulcerative

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, with a prevalence exceeding 400 per 100 000 in North America. Individuals with UC have a lower life expectancy and are at increased risk for colectomy and colorectal cancer.. UC impairs quality of life secondary to inflammation of the colon causing chronic diarrhea and rectal bleeding. Extraintestinal manifestations, such as primary sclerosing cholangitis, occur in approximately 27% of patients with UC. People with UC require monitoring of symptoms and biomarkers of inflammation (eg, fecal calprotectin), and require colonoscopy at 8 years from diagnosis for surveillance of dysplasia. Risk stratification by disease location (eg, Montreal Classification) and disease activity (eg, Mayo Score) can guide management of UC. First-line therapy for induction and maintenance of remission of mild to moderate UC is 5-aminosalicylic acid. Moderate to severe UC may require oral corticosteroids for induction of remission as a bridge to medications that sustain remission (biologic monoclonal antibodies against tumor necrosis factor [eg, infliximab], α4β7 integrins [vedolizumab], and interleukin [IL] 12 and IL-23 [ustekinumab]) and oral small molecules that inhibit janus kinase (eg, tofacitinib) or modulate sphingosine-1-phosphate (ozanimod). Despite advances in medical therapies, the highest response to these treatments ranges from 30% to 60% in clinical trials. Within 5 years of diagnosis, approximately 20% of patients with UC are hospitalized and approximately 7% undergo colectomy. The risk of colorectal cancer after 20 years of disease duration is 4.5%, and people with UC have a 1.7-fold higher risk for colorectal cancer compared with the general population. Life expectancy in people with UC is approximately 80.5 years for females and 76.7 years for males, which is approximately 5 years shorter than people without UC.. UC affects approximately 400 of every 100 000 people in North America. An effective treatment for mild to moderate UC is 5-aminosalicylic acid, whereas moderate to severe UC can be treated with advanced therapies that target specific inflammation pathways, including monoclonal antibodies to tumor necrosis factor, α4β7 integrins, and IL-12 and IL-23 cytokines, as well as oral small molecule therapies targeting janus kinase or sphingosine-1-phosphate.

Topics: Adult; Antibodies, Monoclonal; Colitis, Ulcerative; Colorectal Neoplasms; Female; Humans; Inflammation; Male; Mesalamine; Quality of Life; Tumor Necrosis Factor-alpha

Immune cell trafficking is a critical element of the intestinal immune response, both in homeostasis and in pathological conditions associated with inflammatory bowel disease (IBD). This process involves adhesion molecules, chemoattractants and receptors expressed on immune cell surfaces, blood vessels and stromal intestinal tissue as well as signalling pathways, including those modulated by sphingosine 1-phosphate (S1P). The complex biological processes of leukocyte recruitment, activation, adhesion and migration have been targeted by various monoclonal antibodies (vedolizumab, etrolizumab, ontamalimab). Promising preclinical and clinical data with several oral S1P modulators suggest that inhibition of lymphocyte egress from the lymph nodes to the bloodstream might be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including Crohn's disease and ulcerative colitis. Although various questions remain, including the potential positioning of S1P modulators in treatment algorithms and their long-term safety, this novel class of compounds holds great promise. This Review summarizes the critical mediators and mechanisms involved in immune cell trafficking in IBD and the available evidence for efficacy, safety and pharmacokinetics of S1P receptor modulators in IBD and other immune-mediated disorders. Further, it discusses potential future approaches to incorporate S1P modulators into the treatment of IBD.

Topics: Colitis, Ulcerative; Humans; Inflammatory Bowel Diseases; Lysophospholipids; Sphingosine

Topics: Acetates; Clinical Trials as Topic; Colitis, Ulcerative; Humans; Indans; Indoles; Lysophospholipids; Oxadiazoles; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; T-Lymphocytes

Sphingosine-1-phosphate (S1P) belongs to the group of biologically active sphingolipids. Because of its ability to regulate the migration of lymphocytes, S1P constitutes an important element of pathophysiology of several diseases, such as: lupus erythematosus, multiple sclerosis or inflammatory bowel diseases. Inflammatory bowel diseases (IBD) are the group of chronic and recurrent diseases of the gastrointestinal tract. The most common among IBD are: Crohn’s disease and ulcerative colitis. Drugs that are currently used in the therapy of IBD alleviate symptoms, improve patients’ quality of life and induce remission but their efficacy is not satisfactory. Modulators of S1P receptors constitu­te an emerging option in the therapy of IBD. In this review we will discuss the role of S1P, its receptor and enzymes that participate in the metabolism of S1P under physiological conditions and in the course of IBD. Moreover, we will sum up the results of preclinical and clinical studies on S1P receptors modulators in IBD.. Sfingozyno-1-fosforan (S1P) jest przedstawicielem sfingolipidów o wysokiej aktywno-ści biologicznej. Ze względu na swój wpływ na migrację komórek odpornościowych uznawany jest za istotny element w patogenezie wielu chorób, takich jak: toczeń układowy, stwardnienie rozsiane czy nieswoiste choroby zapalne jelit (NChZJ). Nieswoiste choroby zapalne jelit to grupa przewlekłych i postępujących schorzeń układu pokarmowego, które przebiegają z okresami zaostrzeń i remisji. Do najczęstszych zalicza się: chorobę Leśniow-skiego-Crohna (ChLC) oraz wrzodziejące zapalenie jelita grubego (WZJG). Obecnie w le-czeniu NChZJ stosuje się związki o działaniu przeciwzapalnym i immunomodulującym, których zadaniem jest złagodzenie objawów oraz wprowadzenie pacjenta w stan remisji. W ramach tego artykułu omówiona zostanie rola S1P, receptora dla S1P oraz enzymów bio-rących udział w jego metabolizmie w warunkach fizjologicznych oraz w przebiegu NChZJ. Ponadto, podsumowane zostaną wyniki badań przedklinicznych i klinicznych nad skutecz-nością modulatorów receptora dla S1P w przebiegu NChZJ.

Topics: Colitis, Ulcerative; Crohn Disease; Humans; Inflammatory Bowel Diseases; Lysophospholipids; Quality of Life; Sphingosine

Ozanimod is approved in multiple countries for the treatment of adults with either relapsing multiple sclerosis or moderately to severely active ulcerative colitis. Ozanimod is metabolized in humans to form seven active plasma metabolites, including two major active metabolites CC112273 and CC1084037, and an inactive metabolite. Here, the binding and activity of ozanimod and its metabolites across human sphingosine 1-phosphate receptors were determined. Binding affinity was assessed in Chinese hamster ovary cell membranes expressing recombinant human sphingosine 1-phosphate receptors 1 and 5 via competitive radioligand binding using tritium-labeled ozanimod; selectivity via functional potency assessment was performed using [

Topics: Adult; Animals; CHO Cells; Colitis, Ulcerative; Cricetinae; Cricetulus; Humans; Indans; Multiple Sclerosis; Oxadiazoles; Sphingosine; Sphingosine-1-Phosphate Receptors

Primary sclerosing cholangitis (PSC) is characterised by the co-occurrence of inflammatory bowel diseases, particularly ulcerative colitis (UC). We investigated how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)/ceramide axis may predispose patients with PSC, PSC/UC, and UC to carcinogenesis in the ascending and sigmoid colons. The overexpression of miR-125b was accompanied by the upregulation of S1P, ceramide synthases, ceramide kinases, and the downregulation of AT-rich interaction domain 2 in the ascending colon of PSC/UC, which contributed to the progression of high microsatellite instability (MSI-H) colorectal carcinoma. We also showed that the overexpression of sphingosine kinase 2 (SPHK2) and the genes involved in the glycolytic pathway in the sigmoid colon of UC led to the upregulation of Interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29, and NCM460D) with lipopolysaccharide suppressed miR-125b and increased proinflammatory cytokines, whereas the induction of miR-125b activity by either a miR-125b mimetic or lithocholic acid resulted in the inhibition of miR-125b targets. In summary, miR-125b overexpression was associated with an imbalance in the S1P/ceramide axis that can lead to MSI-H cancer progression in PSC/UC. Furthermore, SPHK2 overexpression and a change in the cellular metabolic flux are important players in inflammation-associated colon cancer in UC.

Topics: Caco-2 Cells; Cholangitis, Sclerosing; Colitis, Ulcerative; Colon; Colonic Neoplasms; Humans; Inflammation; MicroRNAs

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with high sphingosine kinase 1(SPHK1) expression in the colon, however its role in pathogenesis of UC is not clearly understood so, the aim of the present study was to clarify the role of SPHK1 and investigate whether the anti-inflammatory effects of metformin in UC is mediated by Sphingosine kinase 1/sphingosine 1 phosphate (S1P) signaling pathway.. Colitis was induced in adult male wistar rats by intra rectal administration of oxazolone in the fifth and seventh days from initial presensitization. Oxazolone treated rats were divided into untreated oxazolone group, metformin and mesalazine treated groups both in a dose of 100 mg/kg/day orally for 21 days. Along with these groups normal control and saline groups were used .Colitis was assessed by colon length, disease activity index (DAI) and histological examination of colontissue. Plasma samples were used to measure S1P.SPHK1 activity, signal transducer and activator of transcription -3(STAT-3), interleukin-6 (IL-6), nitric oxide (NO), myeloperoxidase activity (MPO), reduced glutathione (GSH) and tissue expression of intracellular cell adhesion molecule -1(ICAM-1) and caspase-3 genes were measured in tissue.. Metformin successfully attenuated oxazolone colitis by increasing colon length, decreasing DAI and improved colon histologic picture. Metformin also induced a significant decrease in Plasma SIP, SPHK1 activity, inflammatory, oxidative stress markers, ICAM-1 and Caspase-3 genes expression compared to oxazolone group.. It is revealed that metformin alleviated inflammation and underlying mechanism may result from inhibition of SPHK1/S1P signaling pathway.

Topics: Animals; Colitis, Ulcerative; Colon; Inflammation; Lysophospholipids; Male; Metformin; Oxazolone; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Wistar; Signal Transduction; Sphingosine

Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that is generated by sphingosine kinase 1 (SphK1) and is known to play an important role in inflammation and cancer progression. Moreover, SphK1 and S1P act as upstream mediators of proinflammatory cytokine interleukin 6 (IL-6) and signal transducer and activator of transcription-3 (STAT3). We hypothesized that the expression levels of phosphorylated SphK1 (pSphK1), phosphorylated STAT3 (pSTAT3), and IL-6 are universally higher in CAC patients than in sporadic colorectal cancer (CRC) patients because all of these factors are associated with inflammation. In this study, we determined the expression levels of pSphK1 in patients with sporadic CRC and CAC and clarified the importance of S1P in CAC patients.. We randomly selected 10 sporadic CRC patients and 10 CAC patients who underwent curative resection, and we examined their surgical specimens by immunohistochemistry. We determined the expression levels of pSphK1, pSTAT3, and IL-6 in these samples.. We found pSphK1 expression to be more prevalent in CAC patients (P = 0.019) and to have a higher immunohistochemistry score (P = 0.005) than in sporadic CRC patients. However, the expression of pSTAT3 and IL-6 did not differ between the patient groups.. To our knowledge, this is the first report comparing pSphK1 expression levels in CAC with those in sporadic CRC. The high levels of pSphK1 expression in CAC suggest an important role of S1P in the disease process of CAC.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Colitis, Ulcerative; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Interleukin-6; Lysophospholipids; Male; Middle Aged; Retrospective Studies; Sphingosine; STAT3 Transcription Factor; Up-Regulation

Increased levels of circulating sphingosine-1-phosphate (S1P) have been reported in ulcerative colitis. The objective of this study was to examine the effect of S1P on colonic smooth muscle contractility and how is it affected by colitis.. Colonic inflammation was induced by intrarectal administration of trinitrobenzene sulfonic acid. Five days later colon segments were isolated and used for contractility experiments and immunoblotting.. S1P contracted control and inflamed colon segments and the contraction was significantly greater in inflamed colon segments. S1P-induced contraction was mediated by S1PR1 and S1PR2 in control and S1PR2 in inflamed colon segments. S1PR3 did not play a significant role in S1P-induced contractions in control or inflamed colon. S1PR1, S1PR2 and S1PR3 proteins were expressed in colon segments from both groups. The expression of S1PR1 and S1PR2 was significantly enhanced in control and inflamed colon segments, respectively. S1PR3 levels however were not significantly different between the two groups. Nifedipine significantly reduced S1P-induced contraction in control but not inflamed colon segments. Thapsigargin significantly reduced S1P-induced contraction of the inflamed colon. GF 109203X and Y-27632, alone abolished S1P-induced contraction of the control but not inflamed colon segments. Combination of GF 109203X, Y-27632 and thapsigargin abolished S1P-induced contraction of inflamed colon segments.. S1P contracted control colon via S1PR1 and S1PR2 and inflamed colon exclusively via S1PR2. Calcium influx (control) or release (inflamed) and calcium sensitization are involved in S1P-induced contraction. Exacerbated response to S1P in colitic colon segments may explain altered colonic motility reported in patients and experimental models of inflammatory bowel disease.

Topics: Animals; Calcium; Colitis, Ulcerative; Colon; Disease Models, Animal; Humans; Inflammation; Lysophospholipids; Muscle Contraction; Muscle, Smooth; Rats; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Thapsigargin; Trinitrobenzenesulfonic Acid

Sphingolipids are emerging as important mediators of immune and inflammatory responses. We have previously demonstrated that sphingosine-1-phosphate (S1P) and its synthetic enzyme sphingosine kinase-1 (SK1) play an important role in inflammatory bowel disease. S1P generation is dependent on SK phosphorylation of sphingosine. Generation of sphingosine results only from the breakdown of ceramide by ceramidases (CDase). In this study, we set out to determine the role of neutral CDase (nCDase) in S1P generation and inflammatory bowel disease. To this end, we established nCDase expression is increased in patients with ulcerative colitis. Using the dextran sulfate sodium (DSS)-induced colitis model, we determined nCDase activity increased in colon epithelium, but not submucosa, in wild-type (WT) mice. Following DSS, ceramide levels were elevated in colon epithelium from WT and nCDase(-/-) mice, while S1P levels were significantly elevated only in the epithelium of nCDase(-/-) mice. Similarly, cyclooxygenase-2 (Cox-2) levels were significantly elevated only in the epithelium of nCDase(-/-) mice. Neutral CDase(-/-) mice also exhibited higher endotoxin levels in circulation, as well as higher circulating levels of S1P. This increase in S1P in nCDase(-/-) mice was accompanied by a marked leukocytosis, most notably circulating neutrophils and lymphocytes. Taken together these data demonstrate that loss of nCDase results in an unexpected increase in S1P generation in inflammation, and suggests that nCDase may actually protect against inflammation.

Topics: Animals; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Endotoxins; Humans; Inflammation; Intestinal Mucosa; Leukocytosis; Lysophospholipids; Mice; Mice, Knockout; Neutral Ceramidase; Signal Transduction; Sphingosine

The bioactive lipid sphingosine-1-phosphate (S1P) is emerging as an important mediator of immune and inflammatory responses. S1P formation is catalyzed by sphingosine kinase (SK), of which the SK1 isoenzyme is activated by tumor necrosis alpha (TNF-alpha). SK1 has been shown to be required for mediating TNF-alpha inflammatory responses in cells, including induction of cyclooxygenase 2 (COX-2). Because TNF-alpha and COX-2 are increased in patients with inflammatory bowel disease (IBD), we investigated the role of SK1 in a murine model of colitis. SK1(-/-) mice treated with dextran sulfate sodium (DSS) had significantly less blood loss, weight loss, colon shortening, colon histological damage, and splenomegaly than did wild-type (WT) mice. In addition, SK1(-/-) mice had no systemic inflammatory response. Moreover, WT but not SK1(-/-) mice treated with dextran sulfate sodium had significant increases in blood S1P levels, colon SK1 message and activity, and colon neutrophilic infiltrate. Unlike WT mice, SK1(-/-) mice failed to show colonic COX-2 induction despite an exaggerated TNF-alpha response; thus implicating for the first time SK1 in TNF-alpha-mediated COX-2 induction in vivo. Inhibition of SK1 may prove to be a valuable therapeutic target by inhibiting systemic and local inflammation in IBD.

Topics: Animals; Body Weight; Colitis; Colitis, Ulcerative; Colon; Cyclooxygenase 2; Dextran Sulfate; Erythrocytes; Gene Expression Regulation; Humans; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Spleen; Tumor Necrosis Factor-alpha