Immunosuppressants and TGF-beta 1 accelerated and prolonged the nitric oxide/oxyradicals-dependent suppression by dexamethasone in paw edema of mice.
Dexamethasone (Dex, 0.3 mg/kg, s.c.) did not suppress histamine and ischemic paw edema of mice up to 1 hr. However, given TGF-beta 1 (0.3 microgram/kg, i.p.), Dex suppression appeared early as 30 min (36% and 42%). When Dex (0.1 mg/kg, s.c.) was injected 6 hr before the assay, Dex alone, TGF-beta 1 +/- Dex, FK506 (10 mg/kg, oral) +/- Dex, cyclosporin (CsA, 30 mg/kg, oral) +/- Dex, rapamycin (Rapa, 10 mg/kg, i.p.) +/- Dex, deoxyspergualin (DSP, 10 mg/kg, i.p.) +/- Dex, did not suppress the edemata (less than 11%). Nevertheless, if Dex and TGF-beta 1 were dosed together with one of these immunosuppressants, suppressions of histamine and ischemic edema were 53%, 45% (FK506), 45%, 49% (CsA), 44%, 48% (Rapa) and 39%, 51% (DSP), respectively. Glucocorticoid (GC) receptor (GR) complex contains heat shock proteins such as hsp56 (or CsA-binding protein: CyP-40), hsp70 and hsp90. FK506, Rapa and TGF-beta 1 receptor I (TR-I) bind FK-binding protein-12 (FKBP-12). FK506 and Rapa bind also hsp56. CsA binds CyP-40. DSP binds hsp70 and/or hsp90. These bindings might change or stabilize the conformation of GR complex resulting in edema suppressions. Nitric oxide synthase (NOS) inhibitors, superoxide dismutase (SOD), catalase, mannitol and cycloheximide, reversed the edema suppressions by TGF-beta1 +/- immunosuppressant at 30 min and 6 hr after Dex. Endogenous NO, O2- and/or .OH seemed to be essential for edema suppressions. Our demonstration in vivo may offer a theoretical support for clinicians to adopt combination therapy of immunosuppressant(s) and GC.
Oyanagui
Y
Y
2nd Pharmacology, Drug Develop. Lab. of Fujisawa Pharmaceut. Co., Osaka, Japan.
D000818:Animals; D003907:Dexamethasone / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy* / Q000503:physiopathology; D005528:Foot / Q000098:blood supply; D006636:Histamine Release; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007511:Ischemia / Q000503:physiopathology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D003907:Dexamethasone