Reduction of estrogen production by interleukin-6 in a human granulosa tumor cell line may have implications for endometriosis-associated infertility

Imari Deura, Deura I, Tasuku Harada, Harada T, Taniguchi F, Fuminori Taniguchi, Tomio Iwabe, Iwabe T, Masao Izawa, Izawa M, Naoki Terakawa, Terakawa N
Fertility and sterility · 2005 · vol. 83(4) , pp. 1086–1092 · doi:10.1016/j.fertnstert.2004.12.014 · PMID:15831279 · W2023861301
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Interleukin-6 reduced estrogen production in a human granulosa tumor cell line, suggesting a potential mechanism contributing to endometriosis-associated infertility.

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Abstract

ObjectiveTo examine the effect of interleukin-6 (IL-6) on estrogen production and aromatase activity using a human granulosa tumor cell line (KGN cells). The involvement of the mitogen-activated protein kinase (MAPK) cascade in the inhibitory effects of IL-6 on estrogen production was also evaluated.DesignMolecular and biological studies of KGN cells.SettingDepartment of Obstetrics and Gynecology, Tottori University Hospital, Yonago, Japan.Main outcome measure(s)Gene expression of IL-6 and the IL-6 receptor was analyzed by reverse transcription-polymerase chain reaction and Southern blot analysis. KGN cells were cultured for 48 hours with IL-6 (0.1-10 ng/mL) or IL-6 (10 ng/mL) plus a mitogen activated protein kinase-extracellular signal regulated kinase kinase 1/2 (MEK1/2) inhibitor U0126 (10 microM). Estradiol concentration in the culture supernatants was measured by means of enzyme immunoassay, [1beta-(3)H] androstenedione was added to the cell lysate supernatant, and aromatase activity was determined by measuring the amount of [(3)H] H(2)O released upon the conversion of [1beta-(3)H] androstenedione to estrone. To examine the activation of intracellular signal transduction molecules induced by IL-6, the phosphorylation of Stat3, p38 MAPK, and extracellular signal-regulated kinase 1/2 (ERK1/2) was examined by Western blotting.Result(s)Gene expression of IL-6 and its receptor was detected in KGN cells. Estradiol secretion was significantly inhibited by adding IL-6, which also suppressed aromatase activity to 50% of the control. In addition, pretreatment with U0126 restored the IL-6-induced suppression of aromatase activity. IL-6 markedly enhanced the phosphorylation of ERK1/2, but not Stat3 and p38 MAPK. U0126 markedly reduced the level of the IL-6-induced phosphorylation of ERK1/2.Conclusion(s)These findings demonstrate that IL-6 may reduce estrogen production via the MAPK signal pathway in human granulosa cells. The results may support the notion that IL-6 is related to impaired estrogen biosynthesis in patients with endometriosis.

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Condition tags

endometriosisinfertility

MeSH descriptors

Endometriosis Estradiol Infertility, Female Interleukin-6 Luteal Cells Antigens, CD Antigens, CD Aromatase Aromatase Cell Line, Tumor Cytokine Receptor gp130 Endometriosis Endometriosis Enzyme Activation Enzyme Activation Estradiol Female Humans Infertility, Female Infertility, Female

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