The involvement of hypoxia-inducible factor 1 alpha in Toll-like receptor 7/8-mediated inflammatory response

Nicholas, Sally A.; Sumbayev, Vadim V.

doi:10.1038/cr.2009.44

Cited by 57 publications

(106 citation statements)

References 27 publications

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“…1,3 Although a hypoxic microenvironment is regarded as a hallmark of solid tumors, and hypoxia-stabilized HIF-1a protein contributes to tumor growth, angiogenesis, and metastasis, 4 several groups, including our own, have reported that HIF-1a protein can trigger acute myeloid leukemia (AML) cells to undergo differentiation through a transcription-independent mechanism, inhibiting the progression of AML. [5][6][7][8][9] MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs of around 22 nucleotides in length that posttranscriptionally repress expression of target genes through imperfect base pairing with the 3 0 untranslated region (UTR), leading to the reduced translation and degradation of the mRNA.…”

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confidence: 99%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1a expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1a represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1a-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1a-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1a-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1a regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcriptional factor that consists of the oxygen-sensitive alpha subunit (HIF-1a) and the constitutively expressed beta subunit (HIF-1b), is a master regulator for the cellular adaptive response to oxygen concentration. 1 Under normoxic conditions, proline residues 402 and 564 of the HIF-1a protein are hydroxylated by specific prolyl hydroxylases (PHDs) that utilize O 2 and a-ketoglutarate as co-factors. The hydroxylated HIF-1a protein is subject to ubiquitination by the E3 ubiquitin ligase von Hippel-Lindau (VHL), which leads to its degradation. In contrast, hypoxic conditions cause the accumulation of HIF-1a protein by inhibiting its hydroxylation, and subsequent ubiquitination and degradation. 2 The stabilized HIF-1a protein translocates into the nucleus, where it forms a heterodimer with HIF-1b and modulates the expression of hundreds of genes through binding to hypoxia-responsive elements (HREs; 5 0 -RCGTG-3 0 ) on their promoters. These HIF-1-targeted genes help the cell adapt to hypoxia by influencing processes such as erythropoiesis, angiogenesis, cell metabolism, growth, apoptosis, and differentiation.Intriguingly, HIF-1a has been shown to contribute to the pathogenesis and progression of multiple kinds of diseases, including cancer. 1,3 Although a hypoxic microenvironment is regarded as a hallmark of solid tumors, and hypoxia-stabilized HIF-1a protein contributes to tumor growth, angiogenesis, and metastasis, 4 several groups, including our own, have reported that HIF-1a protein can trigger acute myeloid leukemia (AML) cells to undergo differentiation through a transcription-independent mechanism, inhibiting the progression of AML. [5][6][7][8][9] MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs of around 22 nucleotides in length that posttra...

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confidence: 99%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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“…THP-1 cells are a myeloid monocytic immortalized human cell line which can be differentiated to macrophages and display the major functional properties of primary human innate immune cells. They are often used as a model to study human inflammatory responses, which allows for the possibility of elucidating the interactions of NPs with innate immune cells 5,6 . Localization of metallic NPs within cellular compartments is important in order to understand their role and mechanisms of interaction 5,7 .…”

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confidence: 99%

Microscopic Analysis of the Interaction of Gold Nanoparticles with Cells of the Innate Immune System

García

Sumbayev

Gilliland

et al. 2013

Sci Rep

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Gold nanoparticles (AuNPs) can interfere with some of the biochemical processes of macrophage cells but the mechanisms of action of these potentially medically-relevant effects are still unclear. Here we study the fate of AuNPs interacting with cells derived from the innate immune system. To visualize AuNPs with nanometer resolution without losing sight of the whole morphology of cells we developed a convenient approach that uses electron and ion microscopy techniques. The inspection using an ion beam to selectively cut where the AuNPs were found, allows for determining their intracellular localizations. We studied the cellular uptake of AuNPs, with or without exposure of the cells to Latrunculin-A, a phagocytosis inhibitor. Results indicate a size dependence of the internalization mechanisms for THP-1 cells. The internalization of larger AuNPs was blocked in the presence of Latrunculin-A, although they could attach to the membrane. Smaller AuNPs though were not blocked by actin depending processes.

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“…The universal adaptor MyD88 is also associated with TLR7/8, and is known to promote the generation of ROS. A signaling pathway including Burton's tyrosine kinase (Btk), PLC-1γ, DAG, PI, intracellular Ca 2+ , PKCα/β and Nox was demonstrated to generate subsequent ROS after R-848 administration in THP-1 human myeloid marophages [13] . In our study, the generation of ROS after R-848 administration in cardiomyocytes was demonstrated directly by ROS measurement and indirectly by NAC administration.…”

Section: Discussionmentioning

confidence: 99%

“…Activated NFκB is [12] . This activation is important for the support of cell survival as it protects the effector cells against the depletion of ATP and thus contributes to the production of proinflammatory cytokines [13,14] . In our study, activated HIF1 was also demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…NFκB activation is involved in TLR7/8 downstream signaling through a MyD88-dependent pathway and is necessary in late preconditioning [11] . Recently, it was reported that both TLR4 and TLR7/8 induce accumulation/activation of HIF1α protein through a redox-dependent mechanism [12,13] , and activation of HIF1α is also involved in ischemic late preconditioning [14] . Therefore, the activation of NFκB and HIF1α in R-848-induced late preconditioning was determined, and the role of ROS in this activation and the down-regulated protein of these two transcription factors, inducible nitric oxide synthase (iNOS), were determined.…”

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor 7/8 agonist resiquimod induces late preconditioning in neonatal cardiac myocytes

et al. 2011

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Aim: To investigate whether R-848 (resiquimod, toll-like receptor 7/8 agonist) can induce late preconditioning in neonatal cardiac myocytes. Methods:The protective effects of R-848 on neonatal myocytes against anoxia-reoxygenation-induced injury were tested, and intracellular reactive oxygen species (ROS) were determined. The protein synthesis inhibitor cyclohexamide (CH) and the ROS scavenger N-acetylcysteine (NAC) were used in this model to test if new protein synthesis and oxidative stress were necessary for their cardioprotective effects. The activation of nuclear factor kappa B (NFκB) and hypoxia inducible factor 1 (HIF1) was investigated by electrophoretic mobility shift assays (EMSA), and inducible nitric oxide synthase (iNOS) was assessed by immunoblotting. After iNOS was downregulated by small interfering RNA (siRNA) transfection, the cardioprotective effect was reassessed. Results: ROS were triggered soon after R-848 (0.01-1.0 μg/L) administration, however, the cardioprotective effect of which was induced 24 h later. This protection was abolished by CH or NAC pretreatment. NFκB and HIF1 activation and iNOS up-regulation were involved in this protective mechanism. The cardioprotective effect was also attenuated after iNOS was knocked down. Conclusion: R-848 provided a cardioprotective effect through a late preconditioning mechanism via a ROS/NFκB-HIF1/iNOS-dependent pathway.

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The involvement of hypoxia-inducible factor 1 alpha in Toll-like receptor 7/8-mediated inflammatory response

Cited by 57 publications

References 27 publications

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

Microscopic Analysis of the Interaction of Gold Nanoparticles with Cells of the Innate Immune System

Toll-like receptor 7/8 agonist resiquimod induces late preconditioning in neonatal cardiac myocytes

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