The induction of heat shock proteins (HSP) by cellular stress and the activation of the hypothalamicpituitary-adrenal axis by physiologic stress are biological responses that aid in the maintenance of cellular and organismal homeostasis, respectively. In this report, restraint stress, known to activate the hypothalamic-pituitary-adrenal axis, is shown to induce expression of HSP70 mRNA selectively in the adrenal cortex of the rat. Restraint-induced HSP70 expression in the adrenals is rapid and is preceded by the activation of a protein factor capable of binding to the heat shock transcriptional control element. The ability of restraint to induce HSP70 expression in the adrenal is virtually eliminated in hypophysectomized rats but can be restored by the exogenous administration of adrenocorticotropic hormone. The magnitude of this induction declines as a function of increasing age, which may contribute to a reduced stress tolerance by aged animals. These results support a role for HSP70 in the physiologic stress response mediated by the hypothalamic-pituitary-adrenal axis.The ability of an organism to adapt to stress is a requisite for its survival in an everchanging environment (1). In higher organisms stress results in the activation of the hypothalamic-pituitary-adrenal (HPA) axis. This response is characterized by the secretion ofcorticotropin-releasing hormone from hypothalamic nuclei into the hypophyseal portal system, which, in turn, stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary into the peripheral circulation. ACTH binds to specific adrenocortical receptors, resulting in the rapid release of glucocorticoids into the bloodstream. Glucocorticoids act on a variety of tissues to give rise to their numerous homeostatic effects (2).At the cellular level, heat and other metabolic stressors induce the synthesis of a set of highly conserved proteins termed heat shock proteins (HSPs) (3). This enhanced gene expression occurs as a result of stress-induced activation of one or more heat shock transcription factors (HSFs) (4-6). These proteins bind to a specific DNA sequence, the heat shock element (HSE) (7-10), in the promotor regions of the HSP genes to increase their rate of transcription. HSPs interact with other cellular proteins under normal and stress conditions and are thought to aid in the maintenance of cellular homeostasis (3).Our current knowledge of HSP function is derived largely from studies in cultured cells. Few investigations have used in vivo stress models that might have direct physiologic relevance. In a previous study we demonstrated that, in response to heat stress, HSP70 is preferentially induced in specific brain regions involved in the regulation of HPA function and hypothesized that HSPs are an integral component of the mammalian physiologic stress response (11). In support of this hypothesis, this report demonstrates that a mild physiologic stress, restraint, induces the expression of the major HSP, HSP70, in rat adrenal cortex. We provide ...