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

Zoltán H. Németh, György Haskó, Csaba Szabo, Andrew L. Salzman, E. Sylvester Vizi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)257-261
Number of pages5
JournalBrain Research Bulletin
Volume46
Issue number3
DOIs
StatePublished - Jun 1998
Externally publishedYes

Fingerprint

Dantrolene
Calcium Channel Blockers
Interleukin-12
Interleukin-10
Interferons
Diltiazem
Verapamil
Calcium
Second Messenger Systems
Lipopolysaccharides
Endotoxemia
Occupations
Neurotransmitter Agents
Tumor Necrosis Factor-alpha

Keywords

  • Cytokines
  • Diltiazem
  • Lipopolysaccharide
  • Sepsis
  • Shock
  • Verapamil

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Calcium channel blockers and dantrolene differentially regulate the production of interleukin-12 and interferon-γ in endotoxemic mice. / Németh, Zoltán H.; Haskó, György; Szabo, Csaba; Salzman, Andrew L.; Vizi, E. Sylvester.

In: Brain Research Bulletin, Vol. 46, No. 3, 06.1998, p. 257-261.

Research output: Contribution to journalArticle

Németh, Zoltán H. ; Haskó, György ; Szabo, Csaba ; Salzman, Andrew L. ; Vizi, E. Sylvester. / Calcium channel blockers and dantrolene differentially regulate the production of interleukin-12 and interferon-γ in endotoxemic mice. In: Brain Research Bulletin. 1998 ; Vol. 46, No. 3. pp. 257-261.
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AU - Vizi, E. Sylvester

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AB - 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.

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