Hypothalamic PituitaryAdrenal Axis and Glucocorticoid Responses

A balance within the body between the brain and immune systems is maintained and regulated by the hypothalamic-pituitary-adrenal (HPA) axis and the resultant immunomodulatory hormones, glucocorticoids (Webster et al., 2002). The endogenous glucocorticoid in man is cortisol, whereas in rodents it is corticosterone. The expression of corticotrophin releasing hormone (CRH) in the hypothalamic region of the brain is activated by inflammatory or other stimuli. In turn, CRH stimulates the release of adrenocorticotropin hormone (ACTH) into the bloodstream from the anterior pituitary gland. ACTH then stimulates the synthesis and release of glucocorticoids from the adrenal glands. In order to maintain regulation of this axis, glucocorticoids feed back and downregulate the HPA axis at the level of the hypothalamus and pituitary. In addition to regulation of the immune system, glucocorticoids are also essential for the regulation of several homeostatic systems in the body, including the central nervous system, cardiovascular system, and metabolic homeostasis. Glucocorticoid regulation of the immune system will not be discussed in detail here but has been the subject of another recent review (Webster et al., 2002).

The many functions of glucocorticoids are elicited through the glucocor-ticoid receptor (GR), a cytosolic receptor. This receptor, along with receptors such as the thyroid hormone, mineralocorticoid, estrogen and progesterone receptors, is a member of the nuclear hormone receptor superfamily (Evans, 1988). For GR, the receptor is located in the cytoplasm in a protein complex, which includes Hsp90 and Hsp70, in the absence of ligand. When the ligand binds, GR is released from the protein complex, dimerizes, and translocates to the nucleus. Once in the nucleus, GR regulates gene expression by binding to specific DNA sequences called glucocorticoid response elements (GREs) (Aranda and Pascual, 2001; Schoneveld et al., 2004). GR is able to upregulate gene expression, such as for the gluconeogenic enzyme tyrosine animotransferase (TAT) (Jantzen et al., 1987), through direct DNA binding. However, it can also repress gene activation, such as the POMC gene, by direct binding to DNA sequences called negative GREs (nGREs) (Drouin et al., 1989). GR can also negatively regulate gene expression without direct binding to DNA. In this case, GR interferes with the action of other signaling pathways, such as NF-kB and AP-1. It is through such interference with other signaling pathways that glucocorticoids exert many of their anti-inflammatory actions (McKay and Cidlowski, 1999; Adcock, 2000; De Bosscher et al., 2003; Smoak and Cidlowski, 2004). GR is essential for life, and mice lacking GR die shortly after birth due to defects in lung maturation (Cole et al., 1995). However, mice with a point mutation that inhibits GR dimerization (GRdim/dim) are viable. In these mice, GR functions that require dimerization, such as GREmediated gene activation, are prevented, but GR functions that do not require dimerization, such as interactions with NF-kB and AP-1, are still possible. This suggests that the anti-inflammatory actions of GR mediated through protein-protein interactions rather than direct DNA binding are essential for life (Reichardt et al., 1998).

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