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AB0070 Deciphering the Functions of Sphingosine Kinases and Sphingosine-1-Phosphate Receptors in the Pathogenesis of Autoimmune Diseases: A Systems Immunological Approach

Background Sphingosine kinases (SPHKs) phosphorylate sphingosine (Sph) to sphingosine-1-phosphate (S1P). S1P is a pleiotropic molecule that mediates various cellular activities such as cell growth, division, survival, angiogenesis, etc., S1P is the ligand for any of the five different types of S1P receptors (S1PRs), which are coupled with G-proteins (S1P1-5), on the plasma membrane in both autocrine and paracrine modes. Recent experimental results have revealed that s (SPHK1 & SPHK2) are important for the initiation of various pathophysiological processes that potentially leads to debilitating diseases such as cancer, sepsis, asthma, anaphylaxis and other associated illnesses. Objectives To decipher the disease associated functions of SPHKs and S1PRs in autoimmune diseases such as Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) and Psoriasis (Ps) using systems immunological approaches. Methods Raw microarray expression (Affymetrix CEL) files derived from studies on RA, PsA, and Ps patients were downloaded from the Gene Expression Omnibus (GEO) and analysed by Genespring GX 12.6 software (Agilent, USA). The normalized gene expression values were analysed by Analysis of Variance (ANOVA) at 5% probability (P<0.05) followed by Benjamini Hochberg Multiple Testing Correction. These differentially genes were further filtered by applying standard 2-fold cut-off compared with normal controls. This gene list was investigated by Ingenuity Pathway Analysis (IPA) knowledgebase (Qiagen, USA) for the identification of disease associated gene networks regulated by SPHKs and S1PRs. Results Our results show that SPHK1, S1P4 and S1P5 were up regulated in the lesions of Ps patients. In RA, both S1P3 and S1P4 were up regulated in the synovial biopsies. Conversely, both S1P3 and S1P4 were down regulated in RA patients treated with anti-TNF therapy. However, both SPHKs and S1PRs were not differentially regulated in PsA patients. Conclusions The systems immunological analysis of high throughput microarray data uncovers disease associated roles of SPHKs and S1PRs in RA and Ps. Besides, it is essential to evaluate the levels of S1P in the serum as well as the differential expression of SPHKs and S1PRs in the whole blood samples and target tissues of patients suffering from autoimmune inflammatory diseases to gauge the disease severity and therapeutic outcomes. References Aarthi JJ, Darendeliler MA, Pushparaj PN (2011). Dissecting the Role of S1P/S1PR axis in Health and Disease. J Dent Res. 90(7): 841- 854. Nayak D, Huo Y, Kwang WXT, Pushparaj PN, Kumar SD, Ling EA, Dheen ST (2010). Sphingosine Kinase 1 Regulates the Expression of Proinflammatory Cytokines and Nitric Oxide in Activated Microglia. Neuroscience. 166:132-134. Jayapal M, Kothandaraman N, Hande MP, Pushparaj PN (2012). Deciphering the structure and function of FcɛRI/mast cell axis in the regulation of allergy and anaphylaxis: a functional genomics paradigm. Cell Mol Life Sci. 69 (12): 1917-1929. Acknowledgements This study was supported by the NSTIP strategic technologies program in the Kingdom of Saudi Arabia (KSA) by the Project Number 12-BIO2719-03. The author also acknowledges with thanks the Science and Technology Unit (STU), King Abdulaziz University (KAU) for technical support. Disclosure of Interest P. Pushparaj Grant/research support from: NSTIP Strategic Technologies Program in the Kingdom of Saudi Arabia (KSA) by the Project Number 12-BIO2719-03, L. Damiati: None declared, S. Bahlas: None declared