Midazolam suppresses maturation of murine dendritic cells and priming of lipopolysaccharide-induced t helper 1-type immune response.
BACKGROUND
Dendritic cells (DCs), as antigen-presenting cells, play a key role in the induction and regulation of adaptive immune response. Midazolam is reported to have immunomodulatory properties that affect immune cells. However, the effect of midazolam on DCs has not been characterized. We examined the immunomodulatory properties of midazolam on DC-mediated immune response.


METHODS
After allowing murine bone marrow-derived DCs induced by granulocyte macrophage colony stimulating factor to mature, we analyzed their expression of costimulatory molecules (CD80 and CD86), major histocompatibility complex class II molecules, and the secretion of interleukin-12 p40. In vitro, we evaluated the effect of midazolam on maturing DCs in mixed cell cultures containing DCs and T cells. In vivo, we investigated the contact-hypersensitivity response.


RESULTS
Midazolam suppressed the expression of CD80, CD86, and major histocompatibility complex class II molecules from murine DCs. Treated with midazolam, DCs also secreted less interleukin-12 p40. In mixed cell cultures with CD3-positive T cells, midazolam-treated DCs showed less propensity to stimulate the proliferation of CD3-positive T cells and the secretion of interferon-γ from CD4-positive T cells. Midazolam-treated DCs impaired the induction of contact-hypersensitivity response. Treatment with ligands for peripheral benzodiazepine receptor inhibited the up-regulation of CD80 during DC maturation.


CONCLUSIONS
Midazolam inhibits the functional maturation of murine DCs and interferes with DC induction of T helper 1 immunity in the whole mouse. In addition, it appears that the immunomodulatory effect of midazolam is mediated via the action of midazolam on the peripheral benzodiazepine receptor.
Intensive Care Unit, Osaka University Hospital, Suita, Japan. nohta753@hp-icu.med.osaka-u.ac.jp
Noriyuki
N
Ohta
Yoshifumi
Y
Ohashi
Chihiro
C
Takayama
Takashi
T
Mashimo
Yuji
Y
Fujino
D018686:Anesthetics, Intravenous / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000276:immunology / Q000494:pharmacology*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects
D018686:Anesthetics, Intravenous; D008070:Lipopolysaccharides; D008874:Midazolam