TY  - JOUR
A1  - Jbeily, Nayla
A1  - Suckert, Iris
A1  - Gonnert, Falk A.
A1  - Acht, Benedikt
A1  - Bockmeyer, Clemens L.
A1  - Grossmann, Sascha D.
A1  - Blaess, Markus F.
A1  - Lüth, Anja
A1  - Deigner, Hans-Peter
A1  - Bauer, Michael
A1  - Claus, Ralf A.
T1  - Hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response
JF  - Journal of lipid research
N2  - Plasma secretion of acid sphingomyelinase is a hallmark of cellular stress response resulting in the formation of membrane embedded ceramide-enriched lipid rafts and the reorganization of receptor complexes. Consistently, decompartmentalization of ceramide formation from inert sphingomyelin has been associated with signaling events and regulation of the cellular phenotype. Herein, we addressed the question of whether the secretion of acid sphingomyelinase is involved in host response during sepsis. We found an exaggerated clinical course in mice genetically deficient in acid sphingomyelinase characterized by an increased bacterial burden, an increased phagocytotic activity, and a more pronounced cytokine storm. Moreover, on a functional level, leukocyte-endothelial interaction was found diminished in sphingomyelinase-deficient animals corresponding to a distinct leukocytes' phenotype with respect to rolling and sticking as well as expression of cellular surface proteins.(jlr) We conclude that hydrolysis of membrane-embedded sphingomyelin, triggered by circulating sphingomyelinase, plays a pivotal role in the first line of defense against invading microorganisms. This function might be essential during the early phase of infection leading to an adaptive response of remote cells and tissues.-Jbeily, N., I. Suckert, F. A. Gonnert, B. Acht, C. L. Bockmeyer, S. D. Grossmann, M. F. Blaess, A. Lueth, H.-P. Deigner, M. Bauer, and R. A. Claus. Hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response. J. Lipid Res. 2013. 54: 410-424.
KW  - sphingomyelin phosphodiesterase 1
KW  - inflammation
KW  - sepsis
KW  - gene expression
KW  - survival
KW  - leukocyte-endothelial interaction
KW  - trans-migration
KW  - organ failure
Y1  - 2013
U6  - https://doi.org/10.1194/jlr.M031625
SN  - 0022-2275
VL  - 54
IS  - 2
SP  - 410
EP  - 424
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Kakkassery, Vinodh
A1  - Skosyrski, S.
A1  - Lüth, A.
A1  - Kleuser, Burkhard
A1  - van der Giet, Maria
A1  - Tate, R.
A1  - Reinhard, J.
A1  - Faissner, Andreas
A1  - Joachim, Stephanie Christine
A1  - Kociok, N.
T1  - Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide-Resistant Retinoblastoma Cells
JF  - Pathology & Oncology Research
N2  - Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test (p < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines (p < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR (p < 0.01), but not in WERI Rb1 (p > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism.
KW  - Retinoblastoma
KW  - Sphingosine-1-phosphate
KW  - Chemotherapy resistance
Y1  - 2017
U6  - https://doi.org/10.1007/s12253-017-0360-x
SN  - 1219-4956
SN  - 1532-2807
VL  - 25
IS  - 1
SP  - 391
EP  - 399
PB  - Springer
CY  - Dordrecht
ER  - 
TY  - JOUR
A1  - Lotinun, Sutada
A1  - Kiviranta, Riku
A1  - Matsubara, Takuma
A1  - Alzate, Jorge A.
A1  - Neff, Lynn
A1  - Lüth, Anja
A1  - Koskivirta, Ilpo
A1  - Kleuser, Burkhard
A1  - Vacher, Jean
A1  - Vuorio, Eero
A1  - Horne, William C.
A1  - Baron, Roland
T1  - Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation
JF  - The journal of clinical investigation
N2  - Cathepsin K (CTSK) is secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption. Global deletion of Ctsk in mice decreases bone resorption, leading to osteopetrosis, but also increases the bone formation rate (BFR). To understand how Ctsk deletion increases the BFR, we generated osteoclast- and osteoblast-targeted Ctsk knockout mice using floxed Ctsk alleles. Targeted ablation of Ctsk in hematopoietic cells, or specifically in osteoclasts and cells of the monocyte-osteoclast lineage, resulted in increased bone volume and BFR as well as osteoclast and osteoblast numbers. In contrast, targeted deletion of Ctsk in osteoblasts had no effect on bone resorption or BFR, demonstrating that the increased BFR is osteoclast dependent. Deletion of Ctsk in osteoclasts increased their sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts, which contained elevated levels of sphingosine-l-phosphate (S1P), increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P(1,3) receptor antagonist inhibited these responses. Osteoblasts derived from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio, providing a positive feedback loop that increased the number of osteoclasts. Our data provide genetic evidence that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P.
Y1  - 2013
U6  - https://doi.org/10.1172/JCI64840
SN  - 0021-9738
VL  - 123
IS  - 2
SP  - 666
EP  - 681
PB  - American Society for Clinical Investigation
CY  - Ann Arbor
ER  -