We investigated the effect of transmembrane form of tumor necrosis factor-alpha (TNF) on atherosclerosis in mice. We compared the development of early atherosclerotic lesions in the aortic sinus of (1) TNF-deficient mice that express only a non-cleavable transmembrane form of TNF (tmTNF), (2) wild-type (WT) C57BL/6 mice, and (3) TNF-deficient mice (TNF(-/-)). All mice were fed an atherogenic diet for 20 weeks. Lipid deposition was the most prominent in WT mice (25030 +/- 5693 microm2), tended to be lower in tmTNF mice (13640+/- 2190 microm2, P > 0.05 versus WT mice) and rare in TNF(-/-) mice (1408 +/- 513 microm2, P < 0.05 versus tmTNF and P < 0.01 versus WT). Macrophage accumulation was five-fold lower (P < 0.05) in tmTNF than in WT mice. In addition, the alpha-actin immuno-reactivity of medial smooth muscle cells remained intact in tmTNF mice but not in WT mice. In WT mice, the plasma lipid profile was significantly more atherogenic than that of TNF(-/-) mice (P < 0.05), but not significantly different from that of tmTNF mice (P > 0.05). These results indicated that in contrast to TNF(-/-) mice, mice expressing exclusively tmTNF were not completely protected from early atherosclerotic lesion formation, although their lesions have a less inflammatory state than those of WT mice, which underlines the stronger proinflammatory potential of soluble TNF.