Darbon J M, Oury F, Laredo J, Bayard F
INSERM U168, Department of Endocrinology, CHU Rangueil, Université Paul Sabatier, Toulouse, France.
Biochem Biophys Res Commun. 1989 Sep 15;163(2):1038-46. doi: 10.1016/0006-291x(89)92326-7.
We have investigated the effects of TNF-alpha on FSH-induced LH receptor expression, cAMP and progesterone production in cultured rat granulosa cells. TNF-alpha (0.5-100 ng/ml) inhibits the stimulating action of FSH on LH receptor formation in a dose-dependent manner with an IC50 of 1 ng/ml and an almost complete suppression of LH receptor induction for 50-100 ng/ml TNF-alpha. The inhibitory effect of TNF-alpha is not due to variations in cell number or viability but rather to a reduction of the LH receptor content per cell with no change in binding affinity (KD = 0.8 x 10(-10)M). TNF-alpha also inhibits the FSH-induced cAMP production but at a lower extent, with a maximum reduction of 60% for 100 ng/ml TNF-alpha. Moreover, TNF-alpha impairs the LH receptor formation induced by forskolin, cholera toxin or 8-Bromo-cAMP, indicating that the cytokine also acts at a step distal to FSH receptor and to cAMP formation. Finally, TNF-alpha decreases dramatically the progesterone synthesis that is stimulated by FSH, with a reduction to undetectable levels on and after 10 ng/ml TNF-alpha. These results suggest that TNF-alpha may drastically reduce the capacity of granulosa cells to differentiate upon FSH stimulation and to respond to LH during the physiological ovarian follicular maturation. Such anti-gonadotropic action of TNF-alpha on granulosa cell differentiation may be also relevant to the alteration of ovarian function during physiopathological processes like inflammatory or infection diseases.
我们研究了肿瘤坏死因子-α（TNF-α）对促卵泡激素（FSH）诱导的培养大鼠颗粒细胞中促黄体生成素（LH）受体表达、环磷酸腺苷（cAMP）和孕酮生成的影响。TNF-α（0.5 - 100 ng/ml）以剂量依赖性方式抑制FSH对LH受体形成的刺激作用，半数抑制浓度（IC50）为1 ng/ml，50 - 100 ng/ml的TNF-α几乎完全抑制LH受体的诱导。TNF-α的抑制作用并非由于细胞数量或活力的变化，而是由于每个细胞中LH受体含量的减少，结合亲和力（KD = 0.8×10⁻¹⁰M）无变化。TNF-α也抑制FSH诱导的cAMP生成，但程度较低，100 ng/ml的TNF-α最大降低60%。此外，TNF-α损害了由福斯可林、霍乱毒素或8-溴环磷酸腺苷诱导的LH受体形成，表明该细胞因子也作用于FSH受体和cAMP形成的下游步骤。最后，TNF-α显著降低FSH刺激的孕酮合成，10 ng/ml及更高浓度的TNF-α可使其降至检测不到的水平。这些结果表明，TNF-α可能会大幅降低颗粒细胞在FSH刺激下分化以及在生理性卵泡成熟过程中对LH作出反应的能力。TNF-α对颗粒细胞分化的这种抗促性腺激素作用也可能与炎症或感染性疾病等病理生理过程中卵巢功能的改变有关。
