Endocrine Abstracts

Exposure to high levels of glucocorticoids (GCs) at critical stages in development is thought to compromise immune function in adulthood (1), but the underlying mechanisms are poorly understood. Accordingly, we have examined the effects of perinatal dexamethasone treatment on the expression in the adult thymus of (a) inducible nitric oxide synthase (NOS-2, paradoxically also expressed constitutively in the thymus) which liberates NO, a factor involved in the negative selection of double-positive thymocytes and (b) annexin 1 (ANXA1) which mediates the inhibitory actions of GCs on NOS-2 expression (2). Sprague-Dawley rats were treated with dexamethasone neonatally (1mg/l/kg body weight, i.p., on postnatal days 3, 5 and 7; controls received saline) or prenatally via the mother's drinking water (1mg/l, gestational days 18-21). The pups grew without further intervention until postnatal day 60 (adulthood) when they were killed humanely. The thymus was removed, bisected and stored for analysis of (a) NOS-2 expression (diaphorase histochemistry) and (b) intracellular and cell surface ANXA1 expression (western blot analysis). Postnatal dexamethasone treatment reduced thymic NOS-2 expression (1.2 ± 0.07 vs. 2.1 ± 0.2 positive cells/mm², p<0.01) and markedly increased intracellular ANXA1 (52.0 ± 4.9 vs. 28.9 ± 3.1, arbitrary units p<0.01) but not cell surface ANXA1 (64.4 ± 16.8 vs. 42.4 ± 9.7, p>0.05). In contrast, prenatal dexamethasone treatment had no effect on the expression of either NOS-2 or ANXA1 in the adult thymus. These results suggest there is a critical window during which early life dexamethasone treatment may compromise immune function by exerting long-term effects on the expression of two regulatory proteins, NOS-2 and ANXA1, within the thymus.

1. Bakker, J. et al., J. Neuroimmunology, 2001, 112: 47-54

2. Wu, CC. et al., Proc Natl. Acad. Sci. USA, 1995, 92: 3473-77

We are grateful to the BBSRC and Umm al-qura University for financial support.