EXPRESSION OF INTERLEUKIN-6 IN ATHEROSCLEROTIC LESIONS OF MALE APOE-KNOCKOUT MICE - INHIBITION BY 17-BETA-ESTRADIOL

Increased levels of interleukin-6 (IL-6) have been proposed to contrib ute to a number of pathological disorders, including osteoporosis and Alzheimer's disease. In human atherosclerotic lesions, IL-6 protein an d mRNA have been detected, although the role of IL-6 in plaque formati on is unknown. We have examined the expression pattern of IL-6 mRNA an d secreted protein in male apolipoprotein E-knockout (apoE-KO) mice ao rtas. Furthermore, we have evaluated the effects of 17 beta-estradiol (E2), a vasculoprotective sex steroid hormone, on the secretion of thi s inflammatory cytokine from isolated male apoE-KO mice aortas. The ex pression of IL-6 mRNA was detected by reverse transcription-polymerase chain reaction in the apoE-KO mouse aortas but not in the aortas of a ge-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 wee ks 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 expre ssion with macrophages. Treatment of male apoE-KO mice with E2 for 3 w eeks resulted in a statistically significant 50% reduction in IL-6 sec retion from ex vivo aortic tissue segments. There was no significant c hange in total serum cholesterol and triglyceride levels in the E2-tre ated group compared with placebo-treated controls. These data demonstr ate that (1) IL-6 mRNA and protein are expressed in the atheroscleroti c plaques of apoE-KO mice aortas and (2) IL-6 production is suppressed by E2 treatment, which may contribute to the antiatherosclerotic effe cts of E2 in the apoE-KO mouse model of atherosclerosis.