The brain influences in a major way the immune/inflammatory (I/I) response via the regulation of peripheral nervous system functions and endocrine responses. The hypothalamic-pituitary-adrenal axis which is activated during stress and represents one of the major pathways by which the brain regulates this response. Cells of the immune system carry receptors for a number of hormones, neuropeptides, and neurotransmitters. Changes in neuroendocrine and/or autonomic activities may therefore lead to modulation of the responses of these cells. On the other hand, products of the I/I response influence brain function In addition, immune cells produce a number of hormones and neuropeptides, such as corticotropin-releasing hormone (CRH) and corticotropin (ACTH), which probably act locally as autacoids during both the early and late stages of the I/I process.
CRH is a 41-amino acid peptide, which shows considerable interspecies homology at the amino terminal region and acts as the major physiologic ACTH secretagogue . CRH belongs to a family of peptides with similar activity, such as sauvagine, urotensin I and urocortin . The single CRH and urocortin genes are located in humans on chromosomes 8 and 2, respectively. Initially CRH is synthesized as a larger precursor molecule (191 amino acids in humans) from which it is cleaved at flanking basic amino acid pairs. CRH is synthesized by neurons of the parvocellular hypothalamic paraventricular nuclei and is secreted along with other ACTH secretagogues, such as arginine vasopressin, cholecystokinin, met-enkephalin and dynorphin- into the hypophyseal portal blood via their projecting axons to the median eminence. CRH is also synthesized by anterior pituitary corticotroph cells and stimulates ACTH secretion in an autocrine or paracrine fashion. The magnocellular paraventricular nuclei, which project to the posterior pituitary, also contain CRH-synthesizing neurons. Moreover, CRH is distributed in the brain and spinal cord. The plasma half-life of CRH in humans is four minutes. The secretion of CRH is regulated by inputs from higher centers on which are superimposed the effects of the circadian pacemaker, stress, and glucocorticoid negative feedback. The latter acts at pituitary, hypothalamic and higher levels, such as the hippocampus. ACTH released by CRH leads to secretion of cortisol and other adrenal steroids, such as dehydroepiandrosterone (DHEA) and, transiently, aldosterone.
The immune system reacts to septic or non-septic aggressors with the inflammatory/fever response. This response is microscopically characterized at the local level by dilatation and increased permeability of microvessels, both leading to increased blood flow, exudation of plasma, and migration and accumulation of leukocytes into the inflammatory area. The result of this is to destroy or wall-off the attacking microorganism or the destroyed tissue. The cellular components of the I/I response consist of circulating non-lymphoid leucocytes and lymphocytes and local immune accessory cells. Non-lymphoid leucocytes include the monocytes/macrophages, neutrophils, basophils and eosinophils. Local immune accessory cells include the endothelial cells, tissue fibroblasts, resident macrophages and macrophage-related cells, such as liver Kupffer cells, type A synovial lining cells and central nervous system (CNS) glia cells, as well as the basophil-related mast cells.
Many substances secreted locally in the inflammatory area by the above cells act as auto- or paracrine regulators and/or mediators of the inflammatory response, as well as endocrine messengers between the inflammatory process and other systems such as the CNS, HPA axis and peripheral nervous system. These substances include the vasoactive amines, histamine and serotonin, the kallikrein/kinin system, the Hageman and other clotting factors, the fibrinolytic system, several components of the complement system, as well as eosinophil and platelet activators. They also include cytokines (such as TNF-alpha and -beta, interferon-alpha, -beta, and -gamma), the interleukins 1 through 14 (as well as their binding proteins and natural antagonists), many lipid and glucolipid products of triglyceride metabolism (such as several active products of arachidonic acid, including the endoperoxides, the thromboxanes, prostacyclin, and leukotrienes), as well as platelet activating factor. In addition, active oxygen radicals, nitric oxide and lysosomal constituents like neutral proteases, participate in the inflammatory response.
CRH AND THE I/I RESPONSE
The immune responses, balance between pro- and anti-inflammatory actions (38). Some immune regulators, such as interleukin-1, have been shown to mediate both roles, depending on their site of action .
CRH is involved in opposing and site-specific effects. Traditionally, hypothalamic CRH has been considered to act indirectly on the anti-inflammatory side of this equilibrium, since the end product of the stimulation of the HPA axis is cortisol, which has thoroughly studied anti-inflammatory actions. Moreover, it is known that among the proinflammatory cytokines, interleukin-6 is a potent stimulator of the human HPA axis, and a secretagogue of magnocellular AVP. The administration of interleukin-6 s.c. has lead to considerable elevations in plasma ACTH, cortisol and AVP (39, 40). Recently, we have shown that interleukin-6 in patients with head trauma (an aseptic inflammatory state) and syndrome of inappropriate secretion of antidiuretic hormone, is quantitatively correlated to AVP. The latter is also known to be a potent activator of the HPA axis.
Since CRH is the main stimulator of POMC production from the pituitary, and certain POMC products (like ACTH and beta-endorphin) can directly affect the I/I response, it has been hypothesized that CRH itself might be directly involved with the I/I response. The putative role of CRH in the I/I response was further suggested by the presence of CRH specific binding sites in human lymphocytes secreting POMC-derived peptides (ACTH and beta-endorphin) . By employing the rat air-pouch model of acute aseptic chemical inflammation immunoreactive CRH (IrCRH) was localized in the inflammatory tissue by immunohistochemistry. IrCRH was also found in the cytoplasm of immune accessory cells like macrophages, endothelial cells surrounding vessels, and tissue fibroblasts. By performing immunoneutralization studies in vivo with a highly specific anti-CRH polyclonal antiserum, a significant suppression of the inflammatory response by this antiserum was demonstrated, suggesting that peripheral CRH promotes inflammation . The decrease of the inflammation by this anti-CRH antiserum was similar to the one caused by TNF-alpha immunoneutralization, used as a positive control, since the latter is a well-known mediator of the I/I response. The effects of a combination of anti-CRH and anti-TNF-alpha were not additive, indicating that the two antisera might interfere with a common pathway of the inflammatory response. CRH levels in inflammatory sites are lowered in the presence of somatostatin analogues. Interestingly, locally found somatostatin mediates the glucocorticoid anti-inflammatory effects at the inflammatory sites .
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