Protection from T cell-mediated murine liver failure by phosphodiesterase inhibitors.
Injection of the T cell mitogens concanavalin A (Con A) into nonsensitized or of staphylococcal enterotoxin B (SEB) into D-galactosamine (GalN)-sensitized mice is known to cause fulminant liver failure via a cytokine response syndrome with tumor necrosis factor-alpha (TNF) as the plvotal mediator. We examined in vivo whether the phosphodiesterase (PDE) inhibitors motapizone (PDE3-selective) and rolipram (PDE4-selective) affected cytokine release and hepatic injury after T cell activation. Both motapizone as well as rolipram dose-dependently (0.1-10 mg/kg) attenuated the systemic release of TNF and interferon-gamma as initiated by injection of Con A (25 mg/kg) or SEB (2 mg/kg). Although interleukin-4 production was not affected by motapizone or decreased by rolipram, circulating levels of interleukin-10, however, were significantly increased in PDE inhibitor-treated mice compared with controls. Associated with the suppression of the central mediator TNF, motapizone and rolipram protected mice from liver injury in the Con A as well as in the SEB model. Moreover, the combined administration of motapizone plus rolipram at doses which were ineffective when given alone completely protected mice from GalN/SEB toxicity. These data demonstrate that PDE inhibitors effectively attenuate an inflammatory T cell response in vivo and strongly suggest a therapeutic potential as anti-inflammatory drugs in T cell-related disorders. We conclude that cAMP-elevating drugs shift the balance of T cell-derived cytokines from a proinflammatory to an enhanced anti-inflammatory factor release, thus protecting mice from TNF-mediated hepatic failure.
Gantner
F
F
Faculty of Biology, University of Konstanz, Germany.
Küsters
S
S
Wendel
A
A
Hatzelmann
A
A
Schudt
C
C
Tiegs
G
G
D000818:Animals; D016753:Interleukin-10 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D017093:Liver Failure / Q000517:prevention & control*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4