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* Department of Biochemistry, Kyoritsu College of Pharmacy, Tokyo, Japan; and
Yokohama City University School of Medicine, Fukuura, and
Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan
Alprazolam is a hypnotic/tranquilizer that has been shown to
specifically inhibit the platelet-activating factor (PAF)-induced
aggregation of human platelets. The goal of this study was to elucidate
whether alprazolam modulates IL-1
-initiated responses. For this
purpose we investigated the effects of alprazolam on the
IL-1-induced production of inflammatory cytokines (IL-8 and monocyte
chemoattractant protein 1 (MCP-1)) in a human glioblastoma cell line,
T98G, and explored the signaling pathways involved. We found that
alprazolam inhibited IL-1-elicited MCP-1 production within a range
of 0.1–3 µM. In contrast, it did not inhibit IL-1-induced IL-8
production. Although NF-
B is involved in regulating the
IL-1-induced expression of MCP-1 and IL-8, the degradation of
IB- stimulated by IL-1 was not inhibited by alprazolam.
Alprazolam prevented NF-B from binding to the MCP-1 promoter region
(the A2 and A1 oligonucleotide probes), but binding of NF-B to
IL-8/NF-B was not inhibited. Moreover, alprazolam inhibited
c-Rel/p50 binding to the A2 oligonucleotide probe, but not p50/p65 from
binding to the IL-8/NF-B site. While AP-1 is involved in regulating
the IL-1-induced expression of IL-8, but not MCP-1, alprazolam
potentiated the binding of c-Jun/c-Fos to the AP-1 oligonucleotide
probe. These results show that the inhibition of IL-1-mediated MCP-1
production by alprazolam is mainly due to inhibition of c-Rel/p65 and
c-Rel/p50 binding to the MCP-1 promoter region, since alprazolam did
not affect the IL-1-mediated activation of NF-B (p50/p65) or AP-1
(c-Jun/c-Fos) binding to the IL-8 promoter region. In conclusion, a new
action of alprazolam was elucidated, as shown in the inhibition of
c-Rel/p65- and c-Rel/p50-regulated
transcription.
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