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TNFα affects sphingosine‐1‐phosphate signaling through modulating the expression of the cystic fibrosis transmembrane regulator (CFTR) in vascular smooth muscle cells
Author(s) -
Meissner Anja,
Bolz SteffenSebastian
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1026.36
Subject(s) - cystic fibrosis transmembrane conductance regulator , sphingosine 1 phosphate , sphingosine kinase 1 , microbiology and biotechnology , sphingosine , regulator , cystic fibrosis , sphingosine kinase , signal transduction , chemistry , biology , endocrinology , medicine , receptor , biochemistry , gene
Cellular effects of the ubiquitous signaling molecule sphingosine‐1‐phosphate (S1P) are tightly controlled by a rheostat between the S1P‐generating enzyme sphingosine kinase 1 (Sphk1) and its functional antagonist S1P phosphohydrolase 1 (SPP1). The intracellular localization of SPP1 requires the import of S1P prior to its degradation. We propose that the import into vascular smooth muscle cells (VSMC) critically depends on the cystic fibrosis transmembrane regulator (CFTR) and that changes in CFTR function regulate S1P signaling. In the vasculature, S1P regulates resistance artery myogenic tone and hence, peripheral resistance. Both parameters are increased in heart failure (HF), a finding that is associated with down‐regulation of vascular CFTR. The pro‐inflammatory cytokine TNFα mechanistically links HF and CFTR because (1) TNFα down‐regulates CFTR mRNA and protein expression, (2) increased TNFα expression and down‐regulation of CFTR in resistance arteries co‐localize in HF and (3) sequestration of TNFα with etanercept normalizes CFTR expression. In addition to these genomic effects, TNFα also acutely controls CFTR function through regulation of its membrane abundance. Our data suggest that TNFα‐mediated down‐regulation of CFTR function shifts the balance between S1P synthesis and degradation, leading to enhanced bioavailability and vascular/cellular effects of S1P. Funding: HSFO, CIHR