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Expression of the Interleukin-6 Gene Is Constitutive and Not Regulated by Estrogen in Rat Vascular Smooth Muscle Cells in Culture¹

INSERM U-397, Institut Louis Bugnard, 31403 Toulouse Cedex 4, France

Address all correspondence and requests for reprints to: Dr. Arlette Maret, INSERM U-397, Institut Louis Bugnard, 1 avenue Jean Poulhès, 31403 Toulouse Cedex 4, France. E-mail: maret{at}rangueil.inserm.fr

Vascular smooth muscle cells (SMC) are major constituents of the medial layer of blood vessels and are involved in the development of atherosclerotic plaque. SMC secrete copious IL-6 under basal conditions that can be increased by cytokines such as tumor necrosis factor- and interleukin-1ß (IL-1ß). The goal of our studies was to define the role of estrogen in IL-6 production by SMC. In a first series of experiments, the expression of specific messenger RNAs as well as the production of IL-6 bioactivity by rat SMC in culture could be demonstrated in basal and IL-1-stimulated conditions, but was unaffected by estrogen treatment. Different constructs containing deleted or mutated fragments of the human IL-6 promoter driving luciferase or chloramphenicol acetyltransferase reporter gene were then transiently transfected in these cells. A significant basal activity that was increased 2- to 4-fold after IL-1ß stimulation was observed with the total IL-6 promoter. Deletion analysis indicated that the -158/+11 region containing activator protein-1 and cAMP response element sites was apparently the minimal region of IL-6 promoter to confer both constitutive and IL-1-inducible activities. Site-directed mutagenesis experiments suggest that basal activity is dependent upon the promoter sequence -158 to -112 containing the nuclear factor (NF)-IL6(-153) and Sp1 sites, whereas IL-1ß stimulation would depend on the residual -112 nucleotides containing NF-IL6(-75) and NF-B sites. In contrast to the down-regulation of IL-6 expression by estrogen described in osteoblasts, ethinyl estradiol as well as 17ß-estradiol did not influence stimulated IL-6 activity in our experimental conditions whatever the construct tested, even when either estrogen receptor or ß was overexpressed. Thus, the atheroprotective properties of estrogen are probably not mediated through the regulation of IL-6 production by SMC.

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