Differential effect of dexamethasone on interleukin 1 beta- and cyclic AMP-triggered expression of GTP cyclohydrolase I in rat renal mesangial cells

1 Endogenous synthesis of tetrahydrobiopterin (BH4) is an essential requirement for cytokine-stimulated nitric oxide (NO) synthesis in rat mesangial cells. GTP cyclohydrolase I, the rate-limiting enzyme in BH4 synthesis, is expressed in renal mesangial cells in response to two principal classes of activating signals. These two groups of activators comprise inflammatory cytokines such as interleukin (IL)-1 beta and agents that elevate cellular levels of cyclic AMP. 2 We examined the action of the potent anti-inflammatory drug dexamethasone on GTP cyclohydrolase I induction in response to IL-1 beta and a membrane-permeable cyclic AMP analogue, N-6, O-2'-dibutyryladenosine 3'-5'-phosphate (Bt(2)cyclic AMP). 3 Nanomolar concentrations of dexamethasone markedly attenuated IL-1 beta-induced GTP cyclohydrolase I mRNA steady state level as well as IL-1 beta-induced GTP cyclohydrolase I protein expression and enzyme activity. In contrast, dexamethasone did not inhibit Bt(2)cyclic AMP-triggered increase in GTP cyclohydrolase I mRNA level and protein expression, and low (1 nM) or high (1 and 10 mu M) doses of dexamethasone consistently increased Bt(2)cyclic AMP-induced GTP cyclohydrolase activity. 4 In summary, these results suggest that glucocorticoids act at several levels, critically dependent on the stimulus used, to control GTP cyclohydrolase I expression.