Cross-talk between vitamin D, estrogen and corticosteroids in glucocorticoid resistant asthma

Introduction Glucocorticoids (GC) are mainstay of therapy in asthma but over 50% of asthmatics do not respond to inhaled or oral glucocorticoids. This makes glucocorticoid resistance in asthma a challenging healthcare problem associated with significant morbidity and life-threatening disease progression. Physiologic and pharmacologic actions of glucocorticoids are mediated through binding to their receptors. Interaction of GC with glucocorticoid response elements regulates transcription of antiinflammatory genes. Glucocorticoid actions are affected by posttranslational modification of glucocorticoid receptor (GR), alterations in GR levels, or by actions that counteract its effects on downstream targets. Interplay between sex steroids and secosteroids such as vitamin D, has been shown to alter anti-inflammatory action of glucocorticoids. Given the structural similarities of steroid hormone molecules and their receptors, their co-localization in cells, and similar mechanisms on gene regulation and signalling, it is possible that cross talk between these molecules affects GC function and GC resistance. In patients with steroid resistant asthma, there appear to be defects in GC induced gene transcription of antiinflammatory mediators such as IL10 and mitogen-activated protein kinase phosphatase-1 (MKP-1). Presence of vitamin D may reverse this defect by enhancing GC mediated transcription of genes of IL10 and MKP-1.Antiinflammatory actions of glucocorticoids may differ by gender. In women asthma may be less responsive to corticosteroid treatment, as oestrogen alters GR levels through protein degradation and suppression of GC mediated transcription of anti-inflammatory proteins, such as MKP1 and glucocorticoid-induced leucine zipper protein (GLIZ). We discuss mechanism of glucocorticoid actions and how oestrogen and vitamin D may affect its function and resistance. Conclusion Glucocorticoid resistant asthma is a complex phenotype and exact mechanism of its resistance is still not clearly understood. Study of interactions of major steroid hormone systems may help us understand the impact of individual hormones in regulation of inflammation in asthma.