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Distinct roles for hematopoietic and extra-hematopoietic sphingosine kinase-1 in inflammatory bowel disease.

Snider AJ, Ali WH, Sticca JA, Coant N, Ghaleb AM, Kawamori T, Yang VW, Hannun YA, Obeid LM - PLoS ONE (2014)

Bottom Line: SK1 leads to generation of sphingosine-1-phosphate (S1P) and potentially the activation of S1P receptors to mediate biologic effects.Our previous studies implicated SK1/S1P in the regulation of inflammatory processes, specifically in inflammatory bowel disease (IBD).Interestingly, we determined that extra-hematopoietic SK1 is necessary for the induction of cyclooxygenase 2 (COX2) in colon epithelium in response to DSS-induced colitis.

View Article: PubMed Central - PubMed

Affiliation: Northport Veterans Affairs Medical Center, Northport, New York, United States of America; Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Sphingosine kinase 1 (SK1), one of two SK enzymes, is highly regulated and has been shown to act as a focal point for the action of many growth factors and cytokines. SK1 leads to generation of sphingosine-1-phosphate (S1P) and potentially the activation of S1P receptors to mediate biologic effects. Our previous studies implicated SK1/S1P in the regulation of inflammatory processes, specifically in inflammatory bowel disease (IBD). These studies were conducted using a total body knockout mouse for SK1 and were unable to determine the source of SK1/S1P (hematopoietic or extra-hematopoietic) involved in the inflammatory responses. Therefore, bone marrow transplants were performed with wild-type (WT) and SK1-/- mice and colitis induced with dextran sulfate sodium (DSS). Irrespective of the source of SK1/S1P, bone marrow or tissue, DSS induced colitis in all mice; however, mice lacking SK1 in both hematopoietic and extra-hematopoietic compartments exhibited decreased crypt damage. Systemic inflammation was assessed, and mice with WT bone marrow demonstrated significant neutrophilia in response to DSS. In the local inflammatory response, mice lacking SK1/S1P in either bone marrow or tissue exhibited decreased induction of cytokines and less activation of STAT3 (signal transducer and activator of transcription 3). Interestingly, we determined that extra-hematopoietic SK1 is necessary for the induction of cyclooxygenase 2 (COX2) in colon epithelium in response to DSS-induced colitis. Taken together our data suggest that hematopoietic-derived SK1/S1P regulates specific aspects of the systemic inflammatory response, while extra-hematopoietic SK1 in the colon epithelium is necessary for the autocrine induction of COX2 in DSS-induced colitis.

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Dual sources of SK1/S1P regulate IL-1β and IL-6 expression in DSS-treated mice.Expression levels of A) IL-1β, B) IL-6, and C) TNFα in colon tissues were determined using real time-RTPCR and normalized to β-actin. Data represent mean ±SEM, n≥3 for each treatment group; *p<0.05, **p<0.01, and ****p<0.001 vs strain untreated, #p<0.05 as compared to WTWTBM DSS. X-axis: regular text refers to the host genotype and the superscript to the bone marrow genotype.
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pone-0113998-g004: Dual sources of SK1/S1P regulate IL-1β and IL-6 expression in DSS-treated mice.Expression levels of A) IL-1β, B) IL-6, and C) TNFα in colon tissues were determined using real time-RTPCR and normalized to β-actin. Data represent mean ±SEM, n≥3 for each treatment group; *p<0.05, **p<0.01, and ****p<0.001 vs strain untreated, #p<0.05 as compared to WTWTBM DSS. X-axis: regular text refers to the host genotype and the superscript to the bone marrow genotype.

Mentions: Induction of pro-inflammatory cytokines and pro-inflammatory mediators such as COX2 and STAT3 in colon tissue have been demonstrated in animal models of colitis and colitis associated cancer (CAC). Our previous results in a total body knockout for SK1 demonstrated that SK−/− mice with DSS-induced colitis exhibited an exaggerated TNFα response but failed to induce COX2 in colon tissue. Moreover, we observed that WT mice but not SK−/− mice induced activation (translocation) of STAT3 (Figure S2). Others have also recently demonstrated that SK1 is required for phosphorylation of STAT3 in CAC [18]. Therefore, in our bone marrow transplant model we sought to determine which source of SK1/S1P was necessary for the induction of pro-inflammatory mediators and downstream signaling events in the colon. To this end, IL-1β, IL-6, and TNFα expression levels were examined in colon tissue from bone marrow transplanted mice. IL1β expression levels increased in all treatment groups; however, this was only statistically significant in WTWTBM mice following DSS-induced colitis (Figure 4A). IL-6 and TNFα expression levels were increased in all treatment groups following DSS-induced colitis (Figure 4B & C); however, the largest increases were observed in WTWTBM mice. The deletion of SK1 from either source resulted in strikingly less IL-1β and IL-6 expression, but not TNFα, upon DSS treatment. Of note, we examined nuclear localization of nuclear factor kappa B (NFκB) in response to DSS in all treatment groups. Despite the differences in cytokine expression there were no significant differences in NFκB localization (data not shown). These data suggest that loss of SK1 in either the hematopoietic or extra-hematopoietic cell populations decreases specific pro-inflammatory cytokines in the colon; thus indicating potential dual sources of SK1/S1P necessary for pro-inflammatory cytokines in response to DSS-treatment.


Distinct roles for hematopoietic and extra-hematopoietic sphingosine kinase-1 in inflammatory bowel disease.

Snider AJ, Ali WH, Sticca JA, Coant N, Ghaleb AM, Kawamori T, Yang VW, Hannun YA, Obeid LM - PLoS ONE (2014)

Dual sources of SK1/S1P regulate IL-1β and IL-6 expression in DSS-treated mice.Expression levels of A) IL-1β, B) IL-6, and C) TNFα in colon tissues were determined using real time-RTPCR and normalized to β-actin. Data represent mean ±SEM, n≥3 for each treatment group; *p<0.05, **p<0.01, and ****p<0.001 vs strain untreated, #p<0.05 as compared to WTWTBM DSS. X-axis: regular text refers to the host genotype and the superscript to the bone marrow genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4252067&req=5

pone-0113998-g004: Dual sources of SK1/S1P regulate IL-1β and IL-6 expression in DSS-treated mice.Expression levels of A) IL-1β, B) IL-6, and C) TNFα in colon tissues were determined using real time-RTPCR and normalized to β-actin. Data represent mean ±SEM, n≥3 for each treatment group; *p<0.05, **p<0.01, and ****p<0.001 vs strain untreated, #p<0.05 as compared to WTWTBM DSS. X-axis: regular text refers to the host genotype and the superscript to the bone marrow genotype.
Mentions: Induction of pro-inflammatory cytokines and pro-inflammatory mediators such as COX2 and STAT3 in colon tissue have been demonstrated in animal models of colitis and colitis associated cancer (CAC). Our previous results in a total body knockout for SK1 demonstrated that SK−/− mice with DSS-induced colitis exhibited an exaggerated TNFα response but failed to induce COX2 in colon tissue. Moreover, we observed that WT mice but not SK−/− mice induced activation (translocation) of STAT3 (Figure S2). Others have also recently demonstrated that SK1 is required for phosphorylation of STAT3 in CAC [18]. Therefore, in our bone marrow transplant model we sought to determine which source of SK1/S1P was necessary for the induction of pro-inflammatory mediators and downstream signaling events in the colon. To this end, IL-1β, IL-6, and TNFα expression levels were examined in colon tissue from bone marrow transplanted mice. IL1β expression levels increased in all treatment groups; however, this was only statistically significant in WTWTBM mice following DSS-induced colitis (Figure 4A). IL-6 and TNFα expression levels were increased in all treatment groups following DSS-induced colitis (Figure 4B & C); however, the largest increases were observed in WTWTBM mice. The deletion of SK1 from either source resulted in strikingly less IL-1β and IL-6 expression, but not TNFα, upon DSS treatment. Of note, we examined nuclear localization of nuclear factor kappa B (NFκB) in response to DSS in all treatment groups. Despite the differences in cytokine expression there were no significant differences in NFκB localization (data not shown). These data suggest that loss of SK1 in either the hematopoietic or extra-hematopoietic cell populations decreases specific pro-inflammatory cytokines in the colon; thus indicating potential dual sources of SK1/S1P necessary for pro-inflammatory cytokines in response to DSS-treatment.

Bottom Line: SK1 leads to generation of sphingosine-1-phosphate (S1P) and potentially the activation of S1P receptors to mediate biologic effects.Our previous studies implicated SK1/S1P in the regulation of inflammatory processes, specifically in inflammatory bowel disease (IBD).Interestingly, we determined that extra-hematopoietic SK1 is necessary for the induction of cyclooxygenase 2 (COX2) in colon epithelium in response to DSS-induced colitis.

View Article: PubMed Central - PubMed

Affiliation: Northport Veterans Affairs Medical Center, Northport, New York, United States of America; Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Sphingosine kinase 1 (SK1), one of two SK enzymes, is highly regulated and has been shown to act as a focal point for the action of many growth factors and cytokines. SK1 leads to generation of sphingosine-1-phosphate (S1P) and potentially the activation of S1P receptors to mediate biologic effects. Our previous studies implicated SK1/S1P in the regulation of inflammatory processes, specifically in inflammatory bowel disease (IBD). These studies were conducted using a total body knockout mouse for SK1 and were unable to determine the source of SK1/S1P (hematopoietic or extra-hematopoietic) involved in the inflammatory responses. Therefore, bone marrow transplants were performed with wild-type (WT) and SK1-/- mice and colitis induced with dextran sulfate sodium (DSS). Irrespective of the source of SK1/S1P, bone marrow or tissue, DSS induced colitis in all mice; however, mice lacking SK1 in both hematopoietic and extra-hematopoietic compartments exhibited decreased crypt damage. Systemic inflammation was assessed, and mice with WT bone marrow demonstrated significant neutrophilia in response to DSS. In the local inflammatory response, mice lacking SK1/S1P in either bone marrow or tissue exhibited decreased induction of cytokines and less activation of STAT3 (signal transducer and activator of transcription 3). Interestingly, we determined that extra-hematopoietic SK1 is necessary for the induction of cyclooxygenase 2 (COX2) in colon epithelium in response to DSS-induced colitis. Taken together our data suggest that hematopoietic-derived SK1/S1P regulates specific aspects of the systemic inflammatory response, while extra-hematopoietic SK1 in the colon epithelium is necessary for the autocrine induction of COX2 in DSS-induced colitis.

Show MeSH
Related in: MedlinePlus