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Vol. 280, Issue 1, 53-60, 1997
Biochemical Pharmacology, 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-
(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-
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.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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