EFFECTS OF CYCLOSPORINE-A AND FK506 ON NITRIC-OXIDE AND TETRAHYDROBIOPTERIN SYNTHESIS IN BACTERIAL LIPOPOLYSACCHARIDE-TREATED J774 MACROPHAGES

We evaluated the effects of the immunosuppressants cyclosporin A (CsA) and FK506 on the synthesis of nitric oxide (NO) induced by bacterial lipopolysaccharide (LPS) in J774 macrophages. CsA and FK506 each inhibited NO production by LPS in a concentration-dependent fashion, but the cytotoxicity was also evident at higher concentrations (100 mu M). Neither CsA nor FK506 had any effect on the activity of NO synthase (NOS) that had already been induced. Findings indicated that CsA and FK506 inhibit the induction of NOS, rather than its catalytic activity. CsA and, to a lesser extent, FK506 increased the synthesis of tetrahydrobiopterin (BH4), an essential cofactor of NOS. Thus, inhibition of NO formation by CsA or FK506 is unlikely to associated with a change in BH4 synthesis caused by these agents in LPS-treated J774 macrophages. (C) 1995 Academic Press, Inc.