Calcium channel blockers and dantrolene differentially regulate the production of interleukin-12 and interferon-γ in endotoxemic mice

Recent studies suggested that transmitters released from the sympathetic nerve terminals can modulate various inflammatory responses by occupation of receptors on immune cells. These neurotransmitters act via alteration of intracellular concentration of second messengers. For instance, 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 concentration ([Ca²⁺](i)). Previously we have demonstrated that the calcium channel blockers verapamil and diltiazem, as well as dantrolene, an agent that blocks the release of calcium from its cytoplasmic stores, inhibits tumor necrosis factor-a (TNF-α) and augments interleukin-10 (IL-10) plasma levels in endotoxemic BALB/c mice. Here we investigated the effects of verapamil, diltiazem, and dantrolene on lipopolysaccharide (LPS)-evoked production of interleukin-12 (IL-12) and interferon-γ (IFN-γ) in BALB/c, C57BL/6 IL-10(+/+), and the IL-10 deficient 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 levels of IL-12 and IFN- γ in BALB/c mice. Similarly to the BALB/c mice, dantrolene increased IL-10 plasma levels in C57BL/6 IL-10(+/+) mice. On the other hand, dantrolene suppressed IL-12 and IFN-γ production in both the C57BL/6 IL-10(+/+) and C57BL/6 IL-10(0/0) mice. These data show that calcium entry blockers and dantrolene differentially regulate IL-12 and IFN-γ production. Furthermore, dantrolene inhibits the IL-12 and IFN-γ response independently of the increased release of IL-10.