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Studies on the Neuroimmune Mechanisms of Glucocorticoid Resistance
These studies are designed to examine interactions between the neuroendocrine and immune systems, specifically, glucocorticoid and proinflammatory cytokine signal transduction pathways and their role in the pathophysiology of mood disorders. Glucocorticoids play an essential role in responses to environmental stressors, serving initially to mobilize bodily responses to challenge and ultimately serving to restrain neuroendocrine as well as immune responses (inflammation). A number of diseases including autoimmune, infectious and inflammatory disorders as well as certain neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids and impaired functioning of the glucocorticoid receptor (GR). Impaired responsiveness to glucocorticoids, in turn, may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone (CRH) and sympathetic nervous system (SNS) pathways. The primary hypothesis of this work is that reduced responsiveness to glucocorticoids is a result of impaired GR function secondary to chronic exposure to proinflammatory cytokines (e.g. IL-1) as may occur in the context of chronic medical illness or chronic stress. Impaired GR function may contribute to hyperactivity of cytokine signaling, that in turn may lead to behavioral impairment (depression) and altered neuronal function. Although proinflammatory cytokines have been shown to inhibit GR function, the signal transduction pathways involved are poorly understood. Mitogen-activated protein kinase (MAPK) pathways such as p38 are stimulated by proinflammatory cytokines as well as other immunoregulatory cytokines including IFN-alpha. P38 has been shown to negatively regulate GR function. In addition, other relevant cytokine signaling pathways such as JNK, NF-kB, STAT and COX pathways may also play a role. Finally, cAMP/protein kinase A (PKA) signal transduction pathways are reportedly involved in enhancing GR function. Moreover, PKA pathways can inhibit cytokine signaling. Thus, reduced PKA activity, which has been found in patients with major depression, may leave cells more vulnerable to GR dysfunction induced by proinflammatory and immunoregulatory cytokines. Enhancement of cAMP/PKA signal transduction may reverse cytokine-induced GR impairment and thus represent a therapeutic strategy to restore glucocorticoid-mediated feedback inhibition of relevant bodily/immune responses. |
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