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

Haskó, György; Deitch, Edwin A.; Németh, Zoltán; Kuhel, David G.; Szabó, Csaba

doi:10.1124/jpet.301.1.103

Cited by 26 publications

(17 citation statements)

References 40 publications

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“…Glyburide can inhibit a broad range of ABC transporters, including ABCA1 and the CFTR protein. 17 At high doses, glyburide inhibited cholesterol efflux in normal fibroblasts but not in Tangier fibroblasts, indicating that glyburide was indeed inhibiting ABCA1 activity (Figure 4). HUVEC efflux was not affected by glyburide treatment, suggesting that cholesterol efflux in endothelial cells was not dependent on ABC-type transporters that are sensitive to glyburide.…”

Section: Abca1 Abcg1 and Endothelial Cholesterol Effluxmentioning

confidence: 94%

Cellular Physiology of Cholesterol Efflux in Vascular Endothelial Cells

2004

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Background— Of the cells that compose the atherosclerotic plaque, vascular endothelial cells are the most resistant to cholesterol accumulation. Cholesterol efflux pathways may play an important role in endothelial cholesterol homeostasis. Methods and Results— We examined the global genetic response of endothelial cells to cholesterol and in particular the contribution of the cholesterol efflux proteins ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor B-I (SR-BI) to endothelial cell cholesterol efflux. The ABCG1 gene is induced in endothelial cells by cholesterol, whereas ABCA1 is not. Using specific chemical inhibitors of ABC transporters and SR-BI, we have shown that neither ABC transporters nor SR-BI is required for apolipoprotein A-1–mediated endothelial cholesterol efflux. Conclusions— Endothelial cells may use nontraditional pathways for cholesterol efflux.

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Section: Abca1 Abcg1 and Endothelial Cholesterol Effluxmentioning

confidence: 94%

Cellular Physiology of Cholesterol Efflux in Vascular Endothelial Cells

2004

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“…For the determination of intracellular TNF-␣, macrophages in 24-well plates were pretreated with adenosine followed by LPS (10 g/ml) stimulation 30 min later. After an additional 6-h incubation, the supernatants were removed and the cells were lysed as described previously (Haskó et al, 2002a). TNF-␣ levels in cell supernatants or cell lysates were determined by ELISA, as we have described previously (Haskó et al, 2002a).…”

Section: Methodsmentioning

confidence: 99%

cDNA Microarray Analysis Reveals a Nuclear Factor-κB-Independent Regulation of Macrophage Function by Adenosine

Németh¹,

Leibovich²,

Deitch³

et al. 2003

J Pharmacol Exp Ther

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Adenosine is released into the extracellular space from nerve terminals and cells subjected to ischemic stress. This nucleoside modulates a plethora of cellular functions via occupancy of specific receptors. Adenosine is also an important endogenous regulator of macrophage function, because it suppresses the production of a number of proinflammatory cytokines by these cells. However, the mechanisms of this anti-inflammatory effect have not been well characterized. We hypothesized that adenosine may exert some of its anti-inflammatory effects by decreasing activation of the transcription factor nuclear factor-B (NF-B), because gene expression of most of the proinflammatory cytokines inhibited by adenosine is dependent on NF-B activation. Using bacterial lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, we found that adenosine as well as adenosine receptor agonists decreased the production of tumor necrosis factor (TNF)-␣, a typical NF-B-regulated cytokine. This effect of adenosine was not due to an action on the process of TNF-␣ release, because adenosine suppressed also the intracellular levels of TNF-␣. However, cDNA microarray analysis revealed that mRNA levels of neither TNF-␣ nor other cytokines were altered by adenosine in either LPS-activated or quiescent macrophages. In addition, although LPS induced expression of a number of other, noncytokine genes, including the adenosine A2b receptor, adenosine did not affect the expression of these genes. Furthermore, adenosine as well as adenosine receptor agonists failed to decrease LPS-induced NF-B DNA binding, NF-B promoter activity, p65 nuclear translocation, and inhibitory B degradation. Together, our results suggest that the anti-inflammatory effects of adenosine are independent of NF-B.Adenosine is an endogenous nucleoside that regulates a variety of physiological processes, including function of the central nervous, circulatory, and gastrointestinal systems (Fredholm et al., 2001). Adenosine has also been implicated as a regulator of a number of pathophysiological conditions, including ischemic processes and inflammatory states (Dubyak and el-Moatassim, 1993;Meldrum et al., 1993;Cohen et al., 2000;Narravula et al., 2000;Chunn et al., 2001;Linden, 2001;Sitaraman et al., 2001;Banerjee et al., 2002;Okusa, 2002;Sitkovsky, 2003). The adenosine modulation of these pathophysiological processes is mediated, in a large part, by effects on the innate immune system (Cronstein, 1994;Haskó et al., 2002b).Monocytes/macrophages have recently emerged as prime targets of the immunomodulatory effects of adenosine Haskó et al., 2002b). Adenosine exerts its biological effects by engaging cell surface receptors. Adenosine receptors have been subdivided according to molecular, biochemical, and pharmacological evidence into four subtypes, which are the A1, A2a, A2b, and A3 receptors (Ralevic and Burnstock, 1998). Cells of the monocyte/macrophage lineage have been documented to express all four adenosine receptors Haskó et al., 2002b). In most in vitro and in vivo ...

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“…Both inhibition of the Na ‡ /H ‡ antiporters by amiloride (NeÂ meth et al 2001) and of ATP-binding cassette transporters by glibenclamide (HaskoÂ et al 2002b) were also reported to suppress IL-12 chain production. The effect of the former was post-translational, as IL-12 chain mRNA levels induced by IFN-® and LPS in the macrophage cell line J774 in the presence of amiloride were not affected (NeÂ meth et al 2001).…”

Section: Ion Channels Pumps and Antiportersmentioning

confidence: 99%

Inhibiting cytokines of the interleukin-12 family: recent advances and novel challenges

Vandenbroeck

Alloza

Gadina³

et al. 2004

Journal of Pharmacy and Pharmacology

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Interleukin-12 (IL-12) and the more recently discovered IL-23 and IL-27 constitute a unique family of structurally related, heterodimeric cytokines that regulate cell-mediated immune responses and T helper 1 (Th1)-type inflammatory reactions. Not surprisingly, the potentiality of treating conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA) through pharmacological interference with IL-12 pathways has received widespread attention. In this review we have examined over 50 substances with reported IL-12 inhibitory effects. We demonstrate that a majority of these belong to a limited number of major functional classes, each of which targets discrete events in the IL-12 biological pathway. Thus, most IL-12 inhibitory substances appear to work either through inhibition of transcription factor NF-µB activation, up-regulation of intracellular cAMP, blockage of posttranslational processing or interference with signal transduction pathways. In addition, cyclophilinbinding drugs, and generic inhibitors of nuclear histone deacetylases, and of ion channels, pumps and antiporters are emerging as potential leads to novel targets for interference with IL-12 production. Many inhibitors of NF-µB and of IL-12 signal transduction have been proven effective in limiting or preventing disease in experimental autoimmune encephalomyelitis (EAE) models of MS. The sharing of the p40 subunit, the IL-12R 1 and components of the signal transduction pathways between IL-12 and IL-23 raises the question as to whether the beneficial effects of various drugs previously ascribed to inhibition of IL-12 may, in fact, have been due to concurrent blockage of both cytokines, or of IL-23, rather than IL-12. Moreover, the homodimeric 2 -form of IL-12, though originally considered to display only antagonistic effects, is now emerging as a pronounced agonist in a variety of inflammatory processes. Reassessment of IL-12 inhibitory compounds is therefore needed to scrutinize their effects on IL-12 ¬ , 2 and IL-23 formation. This is likely to open exciting perspectives to the identification of drugs that target these cytokines either indiscriminately or selectively. The functional diversity of presently available inhibitors should facilitate an unprecedented flexibility in designing future trials for the treatment of IL-12-and IL-23-mediated disorders.

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

Cited by 26 publications

References 40 publications

Cellular Physiology of Cholesterol Efflux in Vascular Endothelial Cells

Cellular Physiology of Cholesterol Efflux in Vascular Endothelial Cells

cDNA Microarray Analysis Reveals a Nuclear Factor-κB-Independent Regulation of Macrophage Function by Adenosine

Inhibiting cytokines of the interleukin-12 family: recent advances and novel challenges

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