Protection from T cell-mediated murine liver failure by phosphodiesterase inhibitors.

TY - JOUR

T1 - Protection from T cell-mediated murine liver failure by phosphodiesterase inhibitors.

AU - Gantner, F

AU - Küsters, S

AU - Wendel, A

AU - Hatzelmann, A

AU - Schudt, C

AU - Tiegs, Gisa

PY - 1997

Y1 - 1997

N2 - 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.

AB - 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.

KW - Animals

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Lymphocyte Activation

KW - Tumor Necrosis Factor-alpha/physiology

KW - T-Lymphocytes/physiology

KW - Interleukin-10/physiology

KW - Interleukin-4/physiology

KW - Liver Failure/prevention & control

KW - Phosphodiesterase Inhibitors/pharmacology

KW - Animals

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Lymphocyte Activation

KW - Tumor Necrosis Factor-alpha/physiology

KW - T-Lymphocytes/physiology

KW - Interleukin-10/physiology

KW - Interleukin-4/physiology

KW - Liver Failure/prevention & control

KW - Phosphodiesterase Inhibitors/pharmacology

M3 - SCORING: Journal article

VL - 280

SP - 53

EP - 60

JO - J PHARMACOL EXP THER

JF - J PHARMACOL EXP THER

SN - 0022-3565

IS - 1

M1 - 1

ER -