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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Inhibitors of ATP-Binding Cassette Transporters Suppress Interleukin-12 p40 Production and Major Histocompatibility Complex II Up-Regulation in Macrophages

György Haskó, Edwin A. Deitch, Zoltán H. Németh, David G. Kuhel and Csaba Szabó
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 103-110; DOI: https://doi.org/10.1124/jpet.301.1.103
György Haskó
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Edwin A. Deitch
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Zoltán H. Németh
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David G. Kuhel
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Csaba Szabó
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Abstract

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 4,4′-diisothiocyanostilbene-2,2′-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 2,2′-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.

Footnotes

  • Abbreviations:
    ABC
    ATP-binding cassette
    SUR
    sulfonylurea receptor
    CFTR
    cystic fibrosis conductance regulator
    MDR
    multidrug resistance protein
    IL
    interleukin
    DIDS
    diisothiocyanostilbene-2,2′-disulfonic acid
    BSP
    sulfobromophthalein
    IFN
    interferon
    LPS
    lipopolysaccharide
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    DPC
    2,2′-iminodibenzoic acid
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    TNF
    tumor necrosis factor
    ELISA
    enzyme-linked immunosorbent assay
    RT-PCR
    reverse transcription-polymerase chain reaction
    PCR
    polymerase chain reaction
    bp
    base pair
    MAPK
    mitogen-activated protein kinase
    JNK
    c-Jun N-terminal protein kinase
    IκB
    inhibitory factor κB
    Ab
    antibody
    MHC
    major histocompatibility complex
    KATP
    ATP-gated potassium
    • Received September 7, 2001.
    • Accepted December 11, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Inhibitors of ATP-Binding Cassette Transporters Suppress Interleukin-12 p40 Production and Major Histocompatibility Complex II Up-Regulation in Macrophages

György Haskó, Edwin A. Deitch, Zoltán H. Németh, David G. Kuhel and Csaba Szabó
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 103-110; DOI: https://doi.org/10.1124/jpet.301.1.103

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Inhibitors of ATP-Binding Cassette Transporters Suppress Interleukin-12 p40 Production and Major Histocompatibility Complex II Up-Regulation in Macrophages

György Haskó, Edwin A. Deitch, Zoltán H. Németh, David G. Kuhel and Csaba Szabó
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 103-110; DOI: https://doi.org/10.1124/jpet.301.1.103
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