DIFFERENTIAL EFFECT OF DEXAMETHASONE ON INTERLEUKIN 1-BETA-TRIGGERED AND CYCLIC AMP-TRIGGERED EXPRESSION OF GTP CYCLOHYDROLASE-I IN RAT RENAL MESANGIAL CELLS

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