Research 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
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
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.
To learn more about active research studies, please click here.