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.

Conclusion: 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.