Activation of a positive feedback loop involving IL-6 and aromatase promotes intratumoral 17ß-estradiol biosynthesis in endometrial carcinoma microenvironment.

Tumor-stroma interactions contribute greatly to intratumoral estrogen biosynthesis in endometrial carcinoma, but the mechanisms involved remain largely unknown. Previous study demonstrated that intratumoral aromatase upregulation in stromal cells participated in this process, but the specific aromatase-regulators have not been reported. In the present study, we found that aromatase expression in intratumoral stroma, but not in tumor epithelium, correlated positively with interleukin 6 (IL-6) expression in cancer epithelial cells by immunohistochemistry, which was confirmed using laser capture microdissection/real-time reverse transcription-PCR. With stimulation by exogenous IL-6, aromarase expression was increased in stromal cells not but not in cancer cells. Aromatase mRNA levels in endometrial cancer cells were not influenced by cocultivation with intratumoral stromal cells. When cocultured with 17ß-estradiol (E2 )-treated cancer cells, aromatase mRNA in stromal cells was significantly elevated and increased IL-6 protein levels were detected in E2 -treated culture medium. Next, we demonstrated that E2 -induced IL-6 production was through cooperation between estrogen receptor α and nuclear factor-kappa B. Furthermore, an IL-6 receptor blocking antibody could attenuate the upregulation of aromatase expression in stromal cells and the E2 concentration in coculture systems of cancer and stromal cells. The results were confirmed by an orthotopic nude endometrial carcinoma model in vivo. These studies elucidated the activation of a positive feedback loop, that is, IL-6 stimulated by E2 in endometrial cancer cells induced aromatase expression in stromal cells, promoting enhanced intratumoral E2 synthesis. Blocking of this tumor-stroma interaction may be a therapeutic strategy to overcome in situ estrogen biosynthesis in endometrial carcinoma.

Correlation between IL-1ß, IL-1Ra gene polymorphism and occurrence of polycystic ovary syndrome infertility.

OBJECTIVE: To explore the relationship between IL-1ß, IL-1Ra gene polymorphism and the occurrence of polycystic ovary syndrome (PCOS) infertility. METHODS: A total of 59 PCOS infertility cases visiting the reproductive center of our hospital from Mar. 2010 to Mar. 2012 and 56 healthy women were selected. ELISA method was used for the detection of IL-1ß, IL-1Ra levels, and the levels of serum supersensitivity C reaction protein (US-CRP), insulin (FINS), follicule-stimulating hormone (FSH) and fasting blood-glucose (FBG) were detected. PCR analysis technology was adopted to detect the gene polymorphism of the 511 site of IL-1ß and the second introne of IL-1Ra. RESULTS: The levels of IL-1ß, IL-1Ra, US-CRP, FINS and FBG in blood serum of patients in PCOS group were significantly higher than those in control group (P<0.05 or P<0.01). The level of FSH in PCOS group was significantly lower than that in control group (P<0.05). The genotypic frequency of T/T, the 511 site of IL-1ß in PCOS group was 42.37%, significantly higher than 12.50% in control group (P<0.01). The frequency of T allele was also significantly higher than that in control group (P<0.01). The genotypic frequency of I/V, the second introne of IL-1Ra in PCOS group was 20.34%, signiciantly higher than 3.57% in control group (P<0.05). The frequency of V allele in PCOS group was significantly higher than that in control group (P<0.05). CONCLUSIONS: T allele of the 511 site of IL-1ß gene and V allele of the second introne of IL-1Ra gene might be the genetic basis of the rising of IL-1ß, IL-1Ra and US-CRP levels in blood serum of PCOS patients, and are associated with the infertility occurrence of PCOS patients.