Endocrine Abstracts

There is evidence from human studies that dehydroepiandrosterone (DHEA) may regulate acquired immunity by promoting a shift towards a T helper type 1 (Th1) phenotype and in innate immunity by suppression of inflammation. Interestingly, circulating levels of DHEA/DHEA-S are significantly reduced in patients with rheumatoid arthritis and systemic lupus erythematosis and are also negatively correlated with age.

Annexin 1 (ANXA1) is a glucocorticoid-induced protein, which is responsible for mediating several anti-inflammatory actions of glucocorticoids. It is highly expressed in cells of the innate immune system and in modest amounts in T lymphocytes, where it too is negatively correlated with age, as are plasma ANXA1 levels in healthy humans. ANXA1 also promotes a Th1 phenotype, as determined by a shift towards a Th2 phenotype in the ANXA1null mouse model compared to wildtype (WT) controls.

The working hypothesis is that circulating levels of DHEA/DHEA-S regulate leukocyte/lymphocyte ANXA1 expression and that with increasing age and decreasing steroid levels, this effect diminishes leading to (i) impaired innate immune responses and (ii) increases susceptibility to auto-immune pathologies.

Western blotting demonstrated activation of annexin 1 by both (A) DHEAS (10⁻⁵ M) and (B) DHEA (10⁻⁸ M) at 4 h and 1 h, respectively. This was demonstrated by an increase in the supernatant fraction in the DHEAS treated cells compared to CT and in the membrane fraction of the DHEA treated cells compared to CT. Annexin 1 was transported from the cytosol (Cyt) across the membrane (Mem) and externalised to the supernatant (Sups) fraction by a mechanism of exocytosis. Polymorphonuclear cells (PMN’s) were isolated from freshly donated human blood-3×10⁶ cells/treatment.

This data identifies a previously unknown mechanism by which adrenal steroids can directly influence the immune system and may reveal clues as to why we experience impaired immunity with increasing age.