Absence of sphingosine kinase 1 alters progression of TNF-alpha induced arthritis (99.25)

Abstract

Abstract Changes in sphingolipid levels can alter cellular functions. Sphingosine 1 phosphate (S1P) and hTNF stimulates COX-2 and PGE2 in fibroblast-like synoviocytes (FLS). In vitro, hTNF and S1P both produce more COX-2 and PGE2 than either separately. Blocking sphingosine kinase 1(SphK1) decreases COX-2 and PGE2 after hTNF stimulation. Our hypothesis is mice overexpressing hTNF without functional SphK1 (hTNF/SphK1-/-) will have less synovial inflammation than mice that overexpress hTNF with functional SphK1 (hTNF/SphK1+/+). Transgenic hTNF mice were crossed with SphK1-/- mice, genotyped and observed, while histological sections were collected to evaluate disease activity. FLS were isolated from the knee joints of WT and SphK1-/- mice, cultured, and stimulated with hTNF. hTNF/SphK1-/- mice had significantly lower arthritis scores, less inflammatory infiltrates and preserved joint spaces compared to hTNF/SphK1+/+ mice. hTNF-stimulated FLS from SphK1-/- mice produced less PGE2 than WT mice. Deletion of SphK1 significantly delays progression and severity of hTNF induced arthritis, synovial proliferation and inflammatory infiltrates. SphK1-/- FLS produced less PGE2 in response to hTNF. Therefore, inhibiting SphK1 is a potential novel therapeutic agent. The project described was supported by Grant Number R01GM062887 from the National Institute of General Medical Sciences and a grant from the ACR REF.