TY - JOUR A1 - Japtok, Lukasz A1 - Schaper, Katrin A1 - Bäumer, Wolfgang A1 - Radeke, Heinfried H. A1 - Jeong, Se Kyoo A1 - Kleuser, Burkhard T1 - Sphingosine 1-Phosphate Modulates Antigen Capture by Murine Langerhans Cells via the S1P(2) Receptor Subtype JF - PLOS ONE N2 - Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P(2) receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P(2) not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions. Citation: Japtok L, Schaper K, Baumer W, Radeke HH, Jeong SK, et al. (2012) Sphingosine 1-Phosphate Modulates Antigen Capture by Murine Langerhans Cells via the S1P(2) Receptor Subtype. PLoS ONE 7(11): e49427. doi:10.1371/journal.pone.0049427 Y1 - 2012 U6 - https://doi.org/10.1371/journal.pone.0049427 SN - 1932-6203 VL - 7 IS - 11 PB - PUBLIC LIBRARY SCIENCE CY - SAN FRANCISCO ER - TY - CHAP A1 - Arlt, Olga A1 - Schwiebs, Anja A1 - Pfarr, Kathrin A1 - Ranglack, Annika A1 - Bouzas, Ferreiros Nerea A1 - Schreiber, Yannick A1 - Neuber, Corinna A1 - Kleuser, Burkhard A1 - Pfeilschifter, Josef M. A1 - Radeke, Heinfried H. T1 - Dynamic interaction between sphingolipid enzymes, S1P and inflammatory cytokine regulation in dendritic cells T2 - NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY Y1 - 2014 SN - 0028-1298 SN - 1432-1912 VL - 387 SP - S91 EP - S91 PB - Springer CY - New York ER - TY - JOUR A1 - Arlt, Olga A1 - Schwiebs, Anja A1 - Japtok, Lukasz A1 - Rueger, Katja A1 - Katzy, Elisabeth A1 - Kleuser, Burkhard A1 - Radeke, Heinfried H. T1 - Sphingosine-1-Phosphate modulates dendritic cell function: focus on non-migratory effects in vitro and in vivo JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Dendritic cells (DCs) are the cutting edge in innate and adaptive immunity. The major functions of these antigen presenting cells are the capture, endosomal processing and presentation of antigens, providing them an exclusive ability to provoke adaptive immune responses and to induce and control tolerance. Immature DCs capture and process antigens, migrate towards secondary lymphoid organs where they present antigens to naive T cells in a well synchronized sequence of procedures referred to as maturation. Indeed, recent research indicated that sphingolipids are modulators of essential steps in DC homeostasis. It has been recognized that sphingolipids not only modulate the development of DC subtypes from precursor cells but also influence functional activities of DCs such as antigen capture, and cytokine profiling. Thus, it is not astonishing that sphingolipids and sphingolipid metabolism play a substantial role in inflammatory diseases that are modulated by DCs. Here we highlight the function of sphingosine 1-phosphate (S1P) on DC homeostasis and the role of SIP and SW metabolism in inflammatory diseases. KW - Sphingosine-1-phosphate KW - Dendritic cells KW - Fingolimod KW - IL-12 KW - Inflammation Y1 - 2014 U6 - https://doi.org/10.1159/000362982 SN - 1015-8987 SN - 1421-9778 VL - 34 IS - 1 SP - 27 EP - 44 PB - Karger CY - Basel ER - TY - JOUR A1 - Schwiebs, Anja A1 - Thomas, Dominique Jeanette A1 - Kleuser, Burkhard A1 - Pfeilschifter, Josef A1 - Radeke, Heinfried H. T1 - Nuclear translocation of SGPP-1 and decrease of SGPL-1 activity contribute to sphingolipid rheostat regulation of inflammatory dendritic cells JF - Mediators of inflammation N2 - A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation. Y1 - 2017 U6 - https://doi.org/10.1155/2017/5187368 SN - 0962-9351 SN - 1466-1861 PB - Hindawi Publishing Corp. CY - London ER -