ESTROGEN MODULATION OF JE MONOCYTE CHEMOATTRACTANT PROTEIN-1 MESSENGER-RNA EXPRESSION IN MURINE MACROPHAGES/

The chemotactic cytokine, monocyte chemoattractant protein-1 (MCP-1), and its murine homologue, JE, have been detected in atherosclerotic le sions but not in normal arteries, implicating that these proinflammato ry cytokines may be involved in the pathogenesis of atherosclerosis. E pidemiologic studies reveal that postmenopausal women receiving estrog en replacement for treatment of osteoporosis have a greatly reduced ri sk of developing cardiovascular disease. Because JE/MCP-1 and estrogen play regulatory roles in the development of atherosclerotic lesions, we chose to examine the effect of estrogen treatment on JE/MCP-1 mRNA expression in macrophages. 17 beta-estradiol (E(2)) inhibited LPS-stim ulated JE/MCP-1 mRNA expression in ANA-1 and J774A.1 murine macrophage cell lines and in thioglycolate-elicited murine peritoneal macrophage s. Inhibition of JE/MCP-1 mRNA ranged from 50 to 90%, with a maximal e ffect occurring at a concentration of 300 pg/ml E(2). Conversely, E(2) had little effect on LPS-stimulated TNF-alpha mRNA production. Treatm ent of LPS-stimulated macrophages with moxestrol, an estrogen agonist, resulted in a similar inhibition, and the addition of the estrogen an tagonist, tamoxifen, reversed E(2) inhibition of JE/MCP-1 mRNA express ion. Progesterone failed to inhibit LPS-induced JE/MCP-1 mRNA expressi on. Immunohistochemical analysis revealed the presence of estrogen rec eptors in ANA-1 cells, indicating that E(2) inhibition of LPS-induced JE/MCP-1 mRNA expression in murine macrophages may be mediated through the estrogen receptor. Thus, another mechanism whereby estrogen exert s antiatherogenic effects may be through prevention of macrophage accu mulation in the atherosclerotic lesion.