Dataset Information

Hemozoin Regulates iNOS Expression by Modulating the Transcription Factor NF-?B in Macrophages.

ABSTRACT: Hemozoin (Hz) is released from ruptured erythrocytes during malaria infection caused by Plasmodium sp., in addition the malaria infected individuals are prone to bacterial sepsis. The molecular interactions between Hz, bacterial components and macrophages remains poorly investigated. In this report, we investigated the combinatorial immune-modulatory effects of phagocytosed Hz, Interferon gamma (IFN?) or lipopolysaccharide (LPS) in macrophages. Macrophages were treated with various concentrations of commercial synthetic Hz, and surprisingly it did not result in inducible nitric oxide synthase (iNOS) expression. However, when macrophages were pretreated with Hz and then challenged with IFN? or LPS, there was a differential impact on iNOS expression. There was an increase in iNOS expression when macrophages were pre-treated with Hz and subsequently treated with IFN? when compared to IFN? alone. Whereas iNOS expression was reduced when Hz phagocytosed macrophages were stimulated with LPS compared to LPS alone. Furthermore, there was an increased activation of NF-?B in Hz phagocytosed macrophages that were challenged with IFN?. The interaction between Hz and macrophages has an impact on iNOS expression.

SUBMITTER: Ranjan R

PROVIDER: S-EPMC5079181 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Hemozoin Regulates iNOS Expression by Modulating the Transcription Factor NF-κB in Macrophages.

Ranjan Ravi R Karpurapu Manjula M Rani Asha A Chishti Athar H AH Christman John W JW

Biochemistry & molecular biology journal 20160814 2

Hemozoin (Hz) is released from ruptured erythrocytes during malaria infection caused by <i>Plasmodium</i> sp., in addition the malaria infected individuals are prone to bacterial sepsis. The molecular interactions between Hz, bacterial components and macrophages remains poorly investigated. In this report, we investigated the combinatorial immune-modulatory effects of phagocytosed Hz, Interferon gamma (IFNγ) or lipopolysaccharide (LPS) in macrophages. Macrophages were treated with various concen ...[more]

PMID: 27790644

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Project description:BackgroundInflammatory mediators play an important role in the occurrence, development, and metastasis of tumors. The aim of the present study was to elucidate the effect of apurinic/apyrimidinic endonuclease 1/reduction-oxidation effector factor-1 (APE1) on inflammatory mediator secretion, which is dependent on the APE1-mediated NLR family pyrin domain containing 3 (NLRP3) regulatory mechanism.MethodsThe human myeloid leukemia mononuclear cell line (THP-1) cells were cultured and polarized to M2 subset macrophages. Enzyme-linked immunosorbent assay was used for determining tumor necrosis factor-? (TNF-?), interleukin (IL)-1?, IL-18, IL-10, and IL-33 levels. Reverse transcription-polymerase chain reaction and western blot were used for evaluating TNF-?, NLR family pyrin domain containing 1 (NLRP1), NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a card expression. Plasmid silencing APE1 gene (APE1shRNA) was synthesized and packaged into lentiviral. For activating inflammasomes, M2-type THP-1 cells were transfected with lentiviral vector APE1shRNA incubated with lipopolysaccharide (LPS) (100 ng/mL)/APE1 inhibitor (E3330, 20 µM) and ATP. Electrophoretic mobility shift assay and dual-luciferase reporter assay were used for determining the interaction between NLRP3 and nuclear factor-?B (NF-?B) molecule.ResultsAPE1 significantly induced LPS-induced pro-inflammatory cytokine production, including TNF-?, IL-1?, and IL18, compared with THP-1 cells without APE1 treatment (P<0.05). APE1 promoted LPS-induced NLRP3 inflammasome activation by modulating the gene transcription of NLRP3-associated molecules. APE1 enhanced LPS-induced NLRP3 inflammasome activation by regulating NLRP3 and caspase-1 protein expression. APE1 improved NLRP3 activity by modulating the interaction between NLRP3 and NF-?B, and the modulation of NF-?B. APE1 promoted LPS-induced NLRP3 inflammasome activation through an NF-?B-dependent pathway.ConclusionsAPE1 regulates the expression of NLRP3 by modulating transcription factor NF-?B and further promoting the secretion of inflammatory mediators IL-1? and IL-18 in macrophages. The findings of the present study provide theoretical and experimental bases for the design of tumor-associated macrophage (TAM)-targeted therapy, with APE1 as the target molecule.

Dataset Information

Hemozoin Regulates iNOS Expression by Modulating the Transcription Factor NF-?B in Macrophages.

Publications

Hemozoin Regulates iNOS Expression by Modulating the Transcription Factor NF-κB in Macrophages.

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