Nitric oxide- and hydrogen peroxide-mediated gene expression by glucocorticoids and FK506 in histamine paw edema of mice.

An immunosuppressant FK506 binds with a component (hsp 56) of glucocorticoid receptor (GR) complex. Dexamethasone (Dex) never suppressed histamine paw edema of mice before 1 hr after its dosing as new protein(s) synthesis is required. However, FK506 (0.01-10 mg/kg, oral) 1.5 hr before 0.1 mg/kg Dex (s.c.), suppressed edema at 30 min. This suppression and that at 3 hr, were abolished by nitric oxide (NO) synthesis inhibitors (1-300 mg/kg). Nitroprusside (NO donor), catalase and molybdate (GR complex stabilizing protease inhibitor) enhanced the suppression. FK506, not cyclosporin A, was demonstrated for the first time in vivo to enhance GR and a hypothesis is proposed that FK506 might enhance GR and AP-1 signalings in a system reciprocally controlled by NO and H2O2.