CALCIUM-CHANNEL BLOCKERS AND DANTROLENE DIFFERENTIALLY REGULATE THE PRODUCTION OF INTERLEUKIN-12 AND INTERFERON-GAMMA IN ENDOTOXEMIC MICE

Recent studies suggested that transmitters released from the sympathet ic nerve terminals can modulate various inflammatory responses by occu pation of receptors on immune cells. These neurotransmitters act via a lteration of intracellular concentration of second messengers. For ins tance, intracellular calcium as a second messenger plays an important role in the regulation of immune responses. Endotoxemia has been shown to be associated with an increase in cytosolic free calcium concentra tion ([Ca2+](i)). Previously we have demonstrated that the calcium cha nnel blockers verapamil and diltiazem, as well as dantrolene, an agent that blocks the release of calcium from its cytoplasmic stores, inhib its tumor necrosis factor-alpha (TNF-alpha) and augments interleukin-1 0 (IL-10) plasma levels in endotoxemic BALB/c mice. Here we investigat ed the effects of verapamil, diltiazem, and dantrolene on lipopolysacc haride (LPS)-evoked production of interleukin-12 (IL-12) and interfero n-gamma (IFN-gamma) in BALB/c, C57BL/6 IL10(+/+), and the IL-10 defici ent C57BL/6 IL-10(0/0) mice. Intraperitoneal (i.p.) pretreatment with dantrolene (20 mg/kg), but not verapamil (10 mg/kg, i.p.) or diltiazem (20 mg/kg, i.p.) suppressed the LPS-induced (80 mg/kg, i.p.) plasma l evels of IL-12 and IFN-gamma in BALB/c mice. Similarly to the BALB/c m ice, dantrolene increased IL-10 plasma levels in C57BL/6 IL-10(+/+) mi ce. On the other hand, dantrolene suppressed IL-12 and IFN-gamma produ ction in both the C57BL/6 IL-10(+/+) and C57BL/6 IL-100/0 mice. These data show that calcium entry blockers and dantrolene differentially re gulate IL-12 and IFN-gamma production. Furthermore, dantrolene inhibit s the IL-12 and IFN-gamma response independently of the increased rele ase of IL-10. (C) 1998 Elsevier Science Inc.