Wang Yifang, Asselin Eric, Tsang Benjamin K
Division of Reproductive Medicine, Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa, Ottawa Health Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada K1Y 4E9.
Biol Reprod. 2002 Jun;66(6):1672-80. doi: 10.1095/biolreprod66.6.1672.
The expression of X-linked inhibitor of apoptosis protein (XIAP), a member of a family of intracellular antiapoptotic proteins, is induced by FSH during follicular development in vivo. Whether the XIAP up-regulation by FSH (100 ng/ml) is a direct action of the gonadotropin and is important in the control of granulosa cell proliferation during follicular growth is unclear. The overall objective of the present study was to examine whether the FSH-induced XIAP expression and granulosa cell proliferation during follicular development is mediated by the secretion and action of intraovarian transforming growth factor alpha (TGFalpha). In rat follicles cultured for 2 and 4 days, FSH stimulated estradiol production, TGFalpha secretion, XIAP expression, and follicular growth. The theca cells are the primary follicular source of FSH-induced TGFalpha, as indicated by in situ hybridization. Intrafollicular injection of a neutralizing anti-TGFalpha antibody (50-200 ng/ml; immunoglobulin G as control) or addition of estradiol-antagonist ICI 182780 (0.5-100 nM) to the culture media suppressed FSH-induced XIAP expression and follicular growth. The effect of ICI 182780 could be partially reversed by high concentrations of estrogen (250 and 500 nM). Whereas TGFalpha (10-20 ng/ml) significantly increased granulosa cell XIAP content and proliferation in primary granulosa cell cultures, FSH alone was ineffective in eliciting the mitogenic response. Our results support the hypothesis that FSH stimulates granulosa cell proliferation via theca TGFalpha secretion and action in response to increased granulosa cell estradiol synthesis, and that XIAP up-regulation in response to FSH suppresses granulosa cell apoptosis and facilitates FSH-induced follicular growth.
细胞内抗凋亡蛋白家族成员X连锁凋亡抑制蛋白（XIAP）的表达，在体内卵泡发育过程中由促卵泡激素（FSH）诱导产生。FSH（100 ng/ml）上调XIAP的表达是否为该促性腺激素的直接作用，以及在卵泡生长过程中对颗粒细胞增殖的控制是否重要，目前尚不清楚。本研究的总体目标是探讨卵泡发育过程中FSH诱导的XIAP表达和颗粒细胞增殖是否由卵巢内转化生长因子α（TGFα）的分泌和作用介导。在培养2天和4天的大鼠卵泡中，FSH刺激雌二醇生成、TGFα分泌、XIAP表达和卵泡生长。原位杂交结果表明，卵泡膜细胞是FSH诱导的TGFα的主要卵泡来源。向培养基中卵泡内注射中和性抗TGFα抗体（50 - 200 ng/ml；以免疫球蛋白G作为对照）或添加雌二醇拮抗剂ICI 182780（0.5 - 100 nM）可抑制FSH诱导的XIAP表达和卵泡生长。高浓度雌激素（250和500 nM）可部分逆转ICI 182780的作用。虽然TGFα（10 - 20 ng/ml）可显著增加原代颗粒细胞培养物中颗粒细胞的XIAP含量和增殖，但单独使用FSH在引发有丝分裂反应方面无效。我们的结果支持以下假设：FSH通过卵泡膜细胞分泌TGFα并发挥作用，以响应颗粒细胞雌二醇合成增加，从而刺激颗粒细胞增殖；并且FSH诱导的XIAP上调可抑制颗粒细胞凋亡并促进FSH诱导的卵泡生长。
