The immune response balances between pro- and anti- inflammatory actions (49). Hypothalamic CRH has been considered to act indirectly in an anti-inflammatory fashion, since the final product of the HPA axis stimulation is cortisol, known for its anti-inflammatory actions. Interleukin 6, a known proinflammatory cytokine, is a potent stimulator of the HPA axis and a secretagogue of magnocellular AVP. The subcutaneous administration of IL-6 in humans causes considerable elevations in plasma ACTH, cortisol and AVP (50). It has been proven that IL-6 levels are increased in patients with head trauma (an aseptic inflammation) and the syndrome of inappropriate secretion of antidiuretic hormone. In this case IL-6 levels are strongly correlated with increased AVP levels (51).The latter is a potent stimulator of the HPA axis.

However, disturbances in the HPA axis activity affect the I/I response. An excessive HPA response (for example a state of stress or relative hypercortisolemia) can increase susceptibility to infectious agents and tumorigenesis but enhance resistance to autoimmune or aseptic inflammatory diseases. On the other hand, a defective HPA axis response (for example relative glucocorticoid deficient state) causes resistance to infections and tumorigenesis but increased susceptibility to autoimmune or aseptic inflammatory diseases. Indeed, these suggestions have been ascertained in Fischer and Lewis rats, two highly inbred strains selected for their resistance (Fischer rats) or susceptibility (Lewis rats) to inflammatory disease. In Lewis rats hypothalamic CRH neurons respond poorly to all neurotransmitters and the overall HPA-axis response to stress is decreased (1). Moreover, CRH deficiency disrupts endogenous glucocorticoid production and enhances allergen-induced airway inflammation and lung mechanical dysfunction in CRH knock-out mice. Thus inherited or acquired CRH deficiency could increase asthma severity in human subjects (52). Hypofunction of the HPA axis was also found in patients with Sjogren's syndrome (53) and sarcoidosis (54).

The presence of CRH–specific binding sites in human lymphocytes secreting POMC-derived peptides (ACTH and β-endorphin) supports the aspect of the direct involvement of CRH in the I/I response (55). By employing the rat air pouch model of carrageenin-induced acute aseptic chemical inflammation immunoreactive (Ir) CRH was detected in the inflamed area but not in the systemic circulation. Corticotropin releasing hormone produced in peripheral inflammatory sites, in contrast to its systemic indirect immunosuppressive effects, acts as an autocrine or paracrine inflammatory cytokine (26). Immunoreactive CRH was found in the synovial lining cell layers and blood vessels from the joints of patients with rheumatoid arthritis and osteoarthritis (56), whereas high CRH levels were found in the synovial fluids of the former patients (57). In addition IrCRH was found in immune accessory cells from uveitic retinas and corpora vitrea from Lewis rats with experimentally induced autoimmune uveitis (23, 58). The local presence of CRH appears to be of pivotal importance in the process of experimental autoimmune uveoretinitis in rodents. Retinas from immunized B10.A mice treated with anti-CRH antibody showed significantly lower apoptosis and Fas and Fas ligand (FasL) expression than placebo-treated animals (59). Thus, CRH in inflammatory sites seems to be involved in the activation of the Fas/FasL system. On the other hand, studies of immunoneutralization in vivo with a highly specific anti-CRH polyclonal antiserum resulted in a major suppression of the inflammatory response (26). Somatostatin analogues have significant anti-inflammatory effects in vivo, associated with suppression of proinflammatory cytokines and neuropeptides. Corticotropin releasing hormone levels at experimentally induced inflammatory sites are lowered in the presence of somatostatin analogues (60). Furthermore, locally produced somatostatin mediates the anti-inflammatory actions of glucocorticoids (61).

Interestingly, CRH-deficient mice are resistant to experimental autoimmune encephalomyelitis (26). This effect of peripheral CRH is independent of its ability to increase corticosterone production, because adrenalectomized wild-type mice had similar disease course and severity as control mice. Thus, it seems that peripheral CRH exerts a proinflammatory effect in experimental autoimmune encephalomyelitis with a selective increase in Th1-type responses indicating a novel contribution of peripheral CRH to the regulation of Th1-mediated inflammation. These findings might have implications for the treatment of Th1-mediated diseases such as multiple sclerosis (62).

Peripheral CRH exerts proinflammatory effects, possibly through mast cell activation. Mast cells are necessary for allergic reactions, but are increasingly implicated in acquired immunity and inflammatory diseases worsened by stress. Acute psychological stress induces CRH-dependent mast cell degranulation. In a similar way CRH causes mast cell degranulation in human skin, releasing great amounts of histamine, which appears to be the principal mediator of the vasodilatory effects of CRH in human skin (63). In addition, CRH is synthesized and secreted by human mast cells acting in autocrine and paracrine fushion, especially in allergic inflammatory disorders exacerbated by stress (64).

Regarding studies on models of septic inflammation, CRH-deficient mice had reduced ileal secretion, histological damage and inflammation in response to clostridium difficile (toxin A). In addition, the content of substance P (a sensory neuropeptide with pivotal role in the mediation and amplification of the inflammatory signal in response to toxin A) at the inflammatory sites is CRH-dependent. These results revealed the major proinflammatory role of CRH in the pathophysiology of toxin A-mediated inflammatory diarrhea and indicate a substance P-linked pathway (65). Furthermore, IrCRH and CRH mRNA as well as CRH binding sites are present in inflammatory cells of rat joint tissue with streptococcal cell wall- and adjuvant-induced arthritis (66, 56).