Expression of Interleukin-6 in Atherosclerotic Lesions of Male ApoE-Knockout Mice

Inhibition by 17ß-Estradiol

From the Departments of Cardiovascular Research (D.A.S., K.K., F.D.S., G.M.R.) and Pharmacology (V.D.V., M.H.-M.), Berlex Biosciences, Richmond, Calif.

Correspondence to Drew A. Sukovich, Department of Cardiovascular Research, Berlex Biosciences, PO Box 4099, 15049 San Pablo Ave, Richmond, CA 94804-0099. E-mail Drew_Sukovich{at}Berlex.com

Abstract—Increased levels of interleukin-6 (IL-6) have been proposed to contribute to a number of pathological disorders, including osteoporosis and Alzheimer's disease. In human atherosclerotic lesions, IL-6 protein and mRNA have been detected, although the role of IL-6 in plaque formation is unknown. We have examined the expression pattern of IL-6 mRNA and secreted protein in male apolipoprotein E–knockout (apoE-KO) mice aortas. Furthermore, we have evaluated the effects of 17ß-estradiol (E2), a vasculoprotective sex steroid hormone, on the secretion of this inflammatory cytokine from isolated male apoE-KO mice aortas. The expression of IL-6 mRNA was detected by reverse transcription–polymerase chain reaction in the apoE-KO mouse aortas but not in the aortas of age-matched control mice. Similarly, the secretion of IL-6 protein from isolated apoE-KO aortic segments was significantly greater than that from aortas of age-matched control animals. The secretion of IL-6 from isolated aortic rings of apoE-KO mice ranging in age from 6 to 48 weeks showed a significant, positive correlation with percent lesion area measured in the same tissue. Immunohistochemical staining of apoE-KO mouse aortic tissue sections demonstrated colocalization of IL-6 expression with macrophages. Treatment of male apoE-KO mice with E2 for 3 weeks resulted in a statistically significant 50% reduction in IL-6 secretion from ex vivo aortic tissue segments. There was no significant change in total serum cholesterol and triglyceride levels in the E2-treated group compared with placebo-treated controls. These data demonstrate that (1) IL-6 mRNA and protein are expressed in the atherosclerotic plaques of apoE-KO mice aortas and (2) IL-6 production is suppressed by E2 treatment, which may contribute to the antiatherosclerotic effects of E2 in the apoE-KO mouse model of atherosclerosis.

Key Words: interleukin 6 • apoE-knockout mice • estrogen • atherosclerosis

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