TY - JOUR T1 - Protection from T Cell-Mediated Murine Liver Failure by Phosphodiesterase Inhibitors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 53 LP - 60 VL - 280 IS - 1 AU - Florian Gantner AU - Sabine Küsters AU - Albrecht Wendel AU - Armin Hatzelmann AU - Christian Schudt AU - Gisa Tiegs Y1 - 1997/01/01 UR - http://jpet.aspetjournals.org/content/280/1/53.abstract N2 - Injection of the T cell mitogens concanavalin A (Con A) into nonsensitized or of staphylococcal enterotoxin B (SEB) intod-galactosamine (GalN)-sensitized mice is known to cause fulminant liver failure via a cytokine response syndrome with tumor necrosis factor-α (TNF) as the pivotal 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-γ 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. The American Society for Pharmacology and Experimental Therapeutics ER -