Protection from T cell-mediated murine liver failure by phosphodiesterase inhibitors.
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Protection from T cell-mediated murine liver failure by phosphodiesterase inhibitors. / Gantner, F; Küsters, S; Wendel, A; Hatzelmann, A; Schudt, C; Tiegs, Gisa.
in: J PHARMACOL EXP THER, Jahrgang 280, Nr. 1, 1, 1997, S. 53-60.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -