HEAT-SHOCK PROTEIN INDUCTION BLOCKS HORMONE-SENSITIVE STEROIDOGENESISIN RAT LUTEAL CELLS

A variety of agents induce heat shock proteins (HSPs) in addition to h eat shock. The heat shock response and its effects on luteal function have not been investigated, but provocatively, many of the agents know n to induce HSPs impair progesterone synthesis in luteal cells. We the refore investigatged whether HSP induction might influence luteal func tion. Rat luteal cells exposed to a ocmmonly used heat shock paradigm (45 degrees C; 10 min) were shown to induce HSP of 70 kDa (HSP-70). He at shock also caused a complete abrogation of LH-sensitive progesteron e and 20 alpha-dihyprogesterone secretion, and blocked steroidogenesis in response to 8-bromo-cAMP and forskolin. In contrast, heat shock ha d no effect on cAMP accumulation in response to LH or forskolin, or on basal progestin secretion. Heat shock inhibition of steroidogenesis w as fully reversed by 22R-hydroxycholesterol (22-OH cholesterol), a cel l- and mitochondrin-permeant cholesterol analog. Inhibition of transcr iption with actinomycin D blocked HSP-70 induction and significantly r eversed the inhibition of steroidogenesis by heat shock treatment. The antisteroidogenic response of heat shock was coincident with inductio n of HSPs and both events were transcriptoin dependent. These findings provide strong evidence that HSP induction inhibits steroidogenesis. The mechanism of the antisteroidogenic action of HSP induction appears to be due to interference with translocation of cholesterol to mitoch ondrial cytochrome P450(scc), a conclusion based on reversal of inhibi tion by 22-OH cholesterol. Because functional luteolysis shows element s similar to a stress response, HSP induction may be a heretofore unre cognized early mediator of luteal regression.