Endogenous
glucocorticoids exert a diverse array of physiological processes including immune-modulatory or anti-inflammatory responses and play an important role in the pathogenesis of inflammatory and
autoimmune diseases. Regulation of inflammatory processes by
glucocorticoids is controlled in a
cytokine-hypothalamo-pituitary-adrenal axis feedback circuit and on the local, cell-type and context-specific local regulatory system. At the tissue level the sensitivity and response to
glucocorticoids are determined by multiple factors: including the local availability to
glucocorticoids transported by blood, the locally-formed bioactive
glucocorticoids (synthesized and metabolized 11β-
hydroxysteroid dehydrogenase enzymes), the number and function of the
glucocorticoid receptor (GR) and the GR affinity to its
ligands. Numerous molecular factors are known to influence the sensitivity of
glucocorticoid response through the GR.
Cytokines are one of the major components that can inhibit GR function and can potentiate the resistance against
glucocorticoids. GR
isoforms, generated by alternative splicing, alternative translation and post-translation modification are further mechanisms which modulate
glucocorticoid signaling. Genetic variants within the GR encoding gene are other potential factors that may influence the susceptibility and severity of autoimmune disorders and may play a key role in individual response to medication. In this review our aim was to summarize our knowledge about the connections between the cell type-specific
glucocorticoid signaling and the local immune system. Prediction of individual sensitivity to
steroids and identification of key players in development of
glucocorticoid resistance are essential in individualized
therapies. The local, tissue-specific
glucocorticoid signaling and its influence by
cytokines may be important in determining the magnitude of inflammatory reactions, and may also be related to the success of
glucocorticoid-containing therapeutic strategies.