Inhibitors of ATP-Binding Cassette Transporters Suppress Interleukin-12 p40 Production and Major Histocompatibility Complex II Up-Regulation in Macrophages
ATP-binding cassette (ABC) transporters are a large family of proteins whose role is to translocate various substances across biological membranes. They include the Tangier disease protein ABC1, sulfonylurea receptors (SUR), multidrug resistance protein (MDR), and cystic fibrosis transmembrane regul...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 301; no. 1; pp. 103 - 110 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.04.2002
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Subjects | |
Online Access | Get full text |
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Summary: | ATP-binding cassette (ABC) transporters are a large family of proteins whose role is to translocate various substances across
biological membranes. They include the Tangier disease protein ABC1, sulfonylurea receptors (SUR), multidrug resistance protein
(MDR), and cystic fibrosis transmembrane regulator (CFTR). In the current study, we investigated the involvement of ABC transporters
in the regulation of lipopolysaccharide (LPS) and/or interferon (IFN)-γ-induced interleukin (IL)-12 p40 and tumor necrosis
factor (TNF)-α production, nitric oxide formation, as well as major histocompatibility complex II up-regulation in macrophages.
The general ABC transporter inhibitor glibenclamide suppressed both IL-12 p40 and nitric oxide production. However, glibenclamide
failed to affect the production of TNF-α. The selective ABC1 inhibitors 4,4â²-diisothiocyanostilbene-2,2â²-disulfonic acid and
sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL-12 p40 production. On the other hand, both the
MDR inhibitor verapamil and CFTR blocker 2,2â²-iminodibenzoic acid failed to suppress the production of IL-12 p40. Furthermore,
selective inhibitors and activators of SURs were without effect. In agreement with the pharmacological data, macrophages expressed
mRNA for ABC1, but not SURs or CFTR. Intracellular levels of IL-12 p40 were decreased by glibenclamide, suggesting that glibenclamide
does not affect IL-12 p40 secretion. The effect of glibenclamide did not involve an interference with the activation of the
p38 and p42/44 mitogen-activated protein kinases or c-Jun kinase. Glibenclamide also suppressed IFN-γ-induced up-regulation
of major histocompatibility complex II. Taken together, our results indicate that ABC proteins regulate LPS and/or IFN-γ-induced
macrophage activation. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.301.1.103 |