Snider Ashley J, Ali Wahida H, Sticca Jonathan A, Coant Nicolas, Ghaleb Amr M, Kawamori Toshihiko, Yang Vincent W, Hannun Yusuf A, Obeid Lina M
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.
Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America.
PLoS One. 2014 Dec 2;9(12):e113998. doi: 10.1371/journal.pone.0113998. eCollection 2014.
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.
鞘氨醇激酶1（SK1）是两种SK酶之一，受到高度调控，并且已被证明是许多生长因子和细胞因子作用的焦点。SK1导致鞘氨醇-1-磷酸（S1P）的生成，并可能激活S1P受体以介导生物学效应。我们之前的研究表明SK1/S1P参与炎症过程的调节，特别是在炎症性肠病（IBD）中。这些研究是使用SK1全身敲除小鼠进行的，无法确定参与炎症反应的SK1/S1P的来源（造血或非造血）。因此，用野生型（WT）和SK1-/-小鼠进行骨髓移植，并用葡聚糖硫酸钠（DSS）诱导结肠炎。无论SK1/S1P的来源是骨髓还是组织，DSS均可在所有小鼠中诱导结肠炎；然而，造血和非造血区室均缺乏SK1的小鼠隐窝损伤减少。评估了全身炎症，具有WT骨髓的小鼠在对DSS的反应中表现出明显的中性粒细胞增多。在局部炎症反应中，骨髓或组织中缺乏SK1/S1P的小鼠细胞因子诱导减少，STAT3（信号转导和转录激活因子3）的激活也较少。有趣的是，我们确定非造血性SK1是结肠上皮细胞响应DSS诱导的结肠炎诱导环氧合酶2（COX2）所必需的。综合我们的数据表明，造血来源的SK1/S1P调节全身炎症反应的特定方面，而结肠上皮中的非造血性SK1是DSS诱导的结肠炎中COX2自分泌诱导所必需的。
