Mast cells play a pivotal role in inflammatory and immediate-type allergic reactions by secreting a variety of potent inflammatory mediators, including sphingosine-1-phosphate (S1P). However, it is not known how S1P is released from cells. Here, we report that S1P is exported from mast cells independently of their degranulation and demonstrate that it is mediated by ATP binding cassette (ABC) transporters. Constitutive and antigen-stimulated S1P release was inhibited by MK571, an inhibitor of ABCC1 (MRP1), but not by inhibitors of ABCB1 (MDR-1, P-glycoprotein). Moreover, downregulation of ABCC1 with small interfering RNA, which decreased its cell surface expression, markedly reduced S1P export from both rat RBL-2H3 and human LAD2 mast cells. Transport of S1P by ABCC1 influenced migration of mast cells toward antigen but not degranulation. These findings have important implications for S1P functions in mast cell-mediated immune responses.secretion ͉ sphingolipids ͉ multidrug resistance ͉ allergic responses ͉ sphingosine kinase S phingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that has been implicated in cancer, immunity, and allergy (1-4). S1P is a ligand for a family of five specific G protein-coupled receptors, designated S1P 1-5 (collectively referred to as S1PRs) (5), through which it regulates many different biological responses, including growth, survival, differentiation, cytoskeleton rearrangements, motility, angiogenesis, vascular maturation, lymphocyte trafficking, and mast cell functions (reviewed in refs. 1-3, 5, and 6). Moreover, like its precursors, sphingosine (Sph) and ceramide, S1P may also have intracellular functions (1, 2, 7). S1P is produced in cells by phosphorylation of Sph, the backbone of all sphingolipids, catalyzed by two closely related Sph kinase (SphK) isoenzymes. SphK1 activity is enhanced by numerous external stimuli, including growth factors, ligands for G protein-coupled receptors, and proinflammatory cytokines, and by cross-linking of Ig receptors (reviewed in refs. 1 and 6). To date, only EGF (8) and cross-linking of Ig receptors (4) have been shown to stimulate SphK2.Although S1P secretion has been demonstrated in only a few types of cells (platelets, astroglial cells, and mast cells) activation of SphK1 involves its translocation to the plasma membrane where its substrate Sph resides (9 -11). Increased S1P formation, in turn, activates S1P receptors on the same and͞or neighboring cells in an autocrine or paracrine manner. It has been demonstrated that this type of ''inside-out'' signaling by S1P is critical for migratory responses of fibroblasts and smooth muscle cells toward PDGF (9, 12) and human breast cancer cells toward EGF (8). Similarly, S1P secreted by mast cells is important for migration of mast cells toward antigen (Ag) and might be involved in the movement of mast cells to sites of inf lammation (13). In addition, S1P provokes human airway smooth muscle contraction and may promote inf lammation and airway remodeling in asthma (14). Because S1P's level...

Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates myriad important cellular processes, including growth, survival, cytoskeleton rearrangements, motility, and immunity. Here we report that treatment of Jurkat and U937 leukemia cells with the pan-sphingosine kinase (SphK) inhibitor N,N-dimethylsphingosine to block S1P formation surprisingly caused a large increase in expression of SphK1 concomitant with induction of apoptosis. Another SphK inhibitor, D,L-threo-dihydrosphingosine, also induced apoptosis and produced dramatic increases in SphK1 expression. However, up-regulation of SphK1 was not a specific effect of its inhibition but rather was a consequence of apoptotic stress. The chemotherapeutic drug doxorubicin, a potent inducer of apoptosis in these cells, also stimulated SphK1 expression and activity and promoted S1P secretion. The caspase inhibitor ZVAD reduced not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of S1P. Apoptotic cells secrete chemotactic factors to attract phagocytic cells, and we found that S1P potently stimulated chemotaxis of monocytic THP-1 and U937 cells and primary monocytes and macrophages. Collectively, our data suggest that apoptotic cells may up-regulate SphK1 to produce and secrete S1P that serves as a "come-and-get-me" signal for scavenger cells to engulf them in order to prevent necrosis.

Sphingosine 1‐phosphate (S1P), produced by two sphingosine kinase isoenzymes (SphK1 and SphK2), regulates many cellular processes important for breast cancer progression by binding to specific S1P receptors. SphK1 is overexpressed in breast cancer, and both estradiol (E2) and epidermal growth factor (EGF) activate SphK1. In this study, we examined how intracellularly produced S1P is secreted from breast cancer cells. Overexpression of SphK1, but not SphK2, increased S1P export from MCF7 cells, and downregulation of expression of SphK1, but not SphK2, decreased its export. Although both E2 and EGF activated SphK1 and increased intracellular S1P, only E2 significantly stimulated S1P secretion. Export of S1P was inhibited by MK571, an inhibitor of ABCC1 (multi‐drug resistant protein 1), and fumitrimorgin C, an inhibitor of ABCG2 (breast cancer resistance protein), but not by the ABCB1 inhibitor, verapamil. In addition, E2‐induced secretion of S1P was blunted by downregulation of ABCC1 or ABCG2. These findings suggest that E2‐induced export of S1P is mediated by specific ABC transporters and may play an important role in multidrug resistance in breast cancer. This work was supported by NIH grants R37 GM043880 and R01CA61774 to SS and 5K12HD055881 to KT.

COVID-19 infection originated in Wuhan, China in December 2019 and crippled human health globally in no time. The public health emergency required urgent efforts to develop and test the efficacy and safety of vaccines to combat the COVID-19 pandemic. The emergency use approval has been granted to COVID-19 vaccines before the completion of conventional phases of clinical trials. However, there is no comprehensive review of safety data reported from the vaccine trials, which is critical information to inform the policies in order to improve uptake of COVID-19 vaccines and mitigate the risk aversion perceived due to the COVID-vaccine side effects. This study aims to systematically review and synthesize the evidence on the safety data from the published COVID-19 vaccine trials. This study followed PRISMA guidelines. We searched three major electronic databases (PubMed, Embase, and Google Scholar) for published studies between Dec 2019 and 2020. Eligible study designs were randomized trials and pre-and post-intervention evaluations. Descriptive findings of included studies were reported stratified by target population, setting, outcomes, and overall results. From PubMed, Embase, WHO database, and Google Scholar screened titles and abstracts, 11 studies were identified in this review. Most of the reactions reported were mild to moderate whereas a few with severe intensity. All reactions resolved within 3-4 days. The & Jaykaran Charan