Impact of sphingosine kinase 2 deficiency on the development of TNF-alpha-induced inflammatory arthritis
- PDF / 262,182 Bytes
- 5 Pages / 595.276 x 790.866 pts Page_size
- 48 Downloads / 151 Views
SHORT COMMUNICATION
Impact of sphingosine kinase 2 deficiency on the development of TNF-alpha-induced inflammatory arthritis DeAnna A. Baker • Jackie Eudaly • Charles D. Smith Lina M. Obeid • Gary S. Gilkeson
•
Received: 17 February 2012 / Accepted: 13 July 2012 Ó Springer-Verlag (outside the USA) 2012
Abstract Sphingolipids are components of the plasma membrane whose metabolic manipulation is of interest as a potential therapeutic approach in a number of diseases. Sphingosine kinase 1 (SphK1), the major kinase that phosphorylates sphingosine to sphingosine-1-phosphate (S1P), was previously shown by our group and others to
D. A. Baker Departments of Microbiology and Immunology, 173 Ashley Avenue MSC 504 Room 203, Charleston, SC 29425, USA J. Eudaly G. S. Gilkeson Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street Suite 912, Charleston, SC 29425, USA C. D. Smith South Carolina College of Pharmacy/Pharmaceutical and Biomedical Sciences, 280 Calhoun Street HCC 617, Charleston, SC 29425, USA L. M. Obeid G. S. Gilkeson Department of Medicine, 96 Jonathan Lucas Street, Suite 803, Charleston, SC 29425, USA L. M. Obeid Departments of Biochemistry and Molecular Biology, 173 Ashley Avenue, P.O. Box 250509, Charleston, SC 29425, USA L. M. Obeid G. S. Gilkeson Medical Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, USA G. S. Gilkeson (&) Division of Rheumatology, Department of Medicine, Medical University of South Carolina, 114 Doughty Street, STB 425, Charleston, SC 29425, USA e-mail: [email protected]
modulate inflammation in murine models of inflammatory arthritis, inflammatory bowel disease and asthma. Sphingosine kinase 2’s (SphK2) impact on inflammation is less well known, as variable results were reported depending on the disease model. A specific SphK2 inhibitor inhibited inflammatory arthritis in one model, while siRNA knockdown of SphK2 worsened arthritis in another. We previously demonstrated that SphK1 deficient mice are protected against development of hTNF-a-induced arthritis. To investigate the role of SphK2 in TNF-a-induced arthritis, we developed SphK2 deficient hTNF-a overexpressing mice and separately treated hTNF-a mice with ABC294640, a SphK2-specific inhibitor. Our data show that genetic inhibition of SphK2 did not significantly impact the severity or progression of inflammatory arthritis, while pharmacologic inhibition of SphK2 led to significantly more severe arthritis. Compared to vehicle-treated mice, ABC294640 treated mice also had less S1P in whole blood and inflamed joint tissue, although the differences were not significant. ABC294640 treatment did not affect SphK1 activity in the inflamed joint while little SphK2 activity was detected in the joint. We conclude that the differences in the inflammatory phenotype in genetic inhibition versus pharmacologic inhibition of SphK2 can be attributed to the amount of ABC294640 used in the experiments versus the impact of acute inhibition of SphK2 with ABC294640 versus genetically induce
Data Loading...
