Tumor necrosis factor-alpha and lymphotoxin-alpha increase macrophage ABCA1 by gene expression and protein stabilization via different receptors.
OBJECTIVE
The tumor necrosis factor superfamily may exert cardioprotective or atherogenic effects, depending on the state of lesion progression. Tumor necrosis factor-alpha (TNF) induces macrophage ATP-binding cassette transporter A1 (ABCA1), a cardioprotective transmembrane protein that exports cellular cholesterol to apolipoprotein A-I. Here we examined the role of TNF receptors (TNFRs) in ABCA1 induction and tested the effects of lymphotoxin-alpha (LT), another TNF family member, on macrophage ABCA1 levels.


METHODS
Primary macrophages taken from mice deficient in TNF receptors were used to determine ABCA1 expression and cholesterol efflux activity in response to treatment with exogenous TNF or LT.


RESULTS
We studied TNFR2(-/-) and TNFR1(-/-)/R2(-/-) mice and found that both receptors are necessary for maximal induction of ABCA1 by TNF. Peritoneal macrophages from TNFR1(-/-)/R2(-/-) mice had no change in ABCA1 mRNA levels when treated with TNF while cells from TNFR2(-/-) mice had ABCA1 mRNA levels that were half that of wild-type (WT) cells. In contrast, incubating TNFR1(-/-)/R2(-/-) mice with LT increased ABCA1 by stabilizing the protein, which was not observed in WT mice and this was associated with downstream signaling through the LTbeta receptor.


CONCLUSIONS
TNF requires both of its receptors to maximally induce ABCA1. Despite previous studies suggesting that LT has proatherogenic properties, we found that LT increases ABCA1 protein in TNFR1(-/-)/R2(-/-) but not WT macrophages and may supplement TNF in enhancing ABCA1-dependent cholesterol export from early atherosclerotic lesions.
Edgel
Kimberly A
KA
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195-8055, United States.
Leboeuf
Renée C
RC
Oram
John F
JF
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D054382:Chemokine CXCL13 / Q000096:biosynthesis; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D008233:Lymphotoxin-alpha; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha