scholarly journals Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 712-722 ◽  
Author(s):  
Philip M. Elks ◽  
Fredericus J. van Eeden ◽  
Giles Dixon ◽  
Xingang Wang ◽  
Constantino Carlos Reyes-Aldasoro ◽  
...  
Keyword(s):  
Cell Function ◽  
Genetic Manipulation ◽  
Tissue Injury ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Site Directed Mutagenesis ◽  
Neutrophil Apoptosis ◽  
Hypoxia Inducible Factor 1Α ◽  
Inflammation Resolution

Abstract The oxygen-sensing transcription factor hypoxia-inducible factor-1α (HIF-1α) plays a critical role in the regulation of myeloid cell function. The mechanisms of regulation are not well understood, nor are the phenotypic consequences of HIF modulation in the context of neutrophilic inflammation. Species conservation across higher metazoans enables the use of the genetically tractable and transparent zebrafish (Danio rerio) embryo to study in vivo resolution of the inflammatory response. Using both a pharmacologic approach known to lead to stabilization of HIF-1α, and selective genetic manipulation of zebrafish HIF-1α homologs, we sought to determine the roles of HIF-1α in inflammation resolution. Both approaches reveal that activated Hif-1α delays resolution of inflammation after tail transection in zebrafish larvae. This delay can be replicated by neutrophil-specific Hif activation and is a consequence of both reduced neutrophil apoptosis and increased retention of neutrophils at the site of tissue injury. Hif-activated neutrophils continue to patrol the injury site during the resolution phase, when neutrophils would normally migrate away. Site-directed mutagenesis of Hif in vivo reveals that hydroxylation of Hif-1α by prolyl hydroxylases critically regulates the Hif pathway in zebrafish neutrophils. Our data demonstrate that Hif-1α regulates neutrophil function in complex ways during inflammation resolution in vivo.

The critical role of mast cell-derived hypoxia-inducible factor-1α in regulating mast cell function

2016 ◽  
Vol 68 (11) ◽  
pp. 1409-1416 ◽  
Author(s):  
Xin Liang ◽  
Guifang Yin ◽  
Yuanyuan Ma ◽  
Ke Xu ◽  
Jianwen Liu ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Function ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α

Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 64-71 ◽  
Author(s):  
Tetsuhiro Horie ◽  
Kazuya Fukasawa ◽  
Takashi Iezaki ◽  
Gyujin Park ◽  
Yuki Onishi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hypoxia Inducible Factor ◽  
Amino Acid Transporters ◽  
Hypoxic Stress ◽  
Gene Encoding ◽  
Brown Adipocytes ◽  
Hypoxia Inducible Factor 1Α ◽  
Brown Adipose

The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.

Chronic in vivo hypoxia in various organs: Hypoxia-inducible factor-1α and apoptosis

2006 ◽  
Vol 342 (3) ◽  
pp. 875-880 ◽  
Author(s):  
Paola Bianciardi ◽  
Monica Fantacci ◽  
Anna Caretti ◽  
Raffaella Ronchi ◽  
Giuseppina Milano ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α

scholarly journals T-cell lineage commitment and cytokine responses of thymic progenitors

Blood ◽  
1995 ◽  
Vol 86 (5) ◽  
pp. 1850-1860 ◽  
Author(s):  
TA Moore ◽  
A Zlotnik
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cultured Cells ◽  
Critical Role ◽  
Cell Lineage ◽  
Lineage Commitment ◽  
Organ Cultures ◽  
Cell Commitment

The earliest steps of intrathymic differentiation recently have been elucidated. It has been reported that both CD4lo (CD44+ CD25- c-kit+ CD3- CD4lo CD8-) and pro-T cells (CD44+ CD25+ c-kit+ CD3- CD4- CD8-, representing the next step in maturation) exhibit germline T-cell receptor beta and gamma loci, suggesting that neither population is exclusively committed to the T-cell lineage. Several groups have shown that CD4lo cells retain the capacity to generate multiple lymphoid lineages in vivo; however, the lineage commitment status of pro-T cells is unknown. To determine when T-cell lineage commitment occurs, we examined the ability of sorted CD4lo and pro-T cells to generate lymphoid lineage cells in vivo or in fetal thymic organ cultures (FTOCs). When intravenously injected into scid mice, CD4lo cells generated both T and B cells, whereas the progeny of pro-T cells contained T cells exclusively. Fetal thymic organ cultures repopulated with CD4lo cells contained both T and natural killer (NK) cells, whereas cultures repopulated with pro-T cells contained T cells almost exclusively. These observations strongly suggest that T-cell lineage commitment occurs during the transition of CD4lo to pro-T cells. Because it is likely that the thymic microenvironment plays a critical role in T-cell commitment, we compared the responses of CD4lo and pro-T cells to various cytokine combinations in vitro, as well as the ability of the cultured cells to repopulate organ cultures. Cytokine combinations that maintained T-cell repopulation potential for both CD4lo and pro-T cells were found. CD4lo cells proliferated best in response to the combination containing interleukin-1 (IL-1), IL-3, IL- 6, IL-7, and stem cell factor (SCF). Unlike CD4lo cells, pro-T cells were much more dependent upon IL-7 for proliferation and FTOC repopulation. However, combinations of cytokines lacking IL-7 were found that maintained the T-cell repopulating potential of pro-T cells, suggesting that, whereas this cytokine is clearly very important for normal pro-T cell function, it is not an absolute necessity during early T-cell expansion and differentiation.

scholarly journals In Vivo Topoisomerase I Inhibition Attenuates the Expression of Hypoxia-Inducible Factor 1α Target Genes and Decreases Tumor Angiogenesis

2011 ◽  
Vol 18 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Eric Guérin ◽  
Wolfgang Raffelsberger ◽  
Erwan Pencreach ◽  
Armin Maier ◽  
Agnès Neuville ◽  
...  
Keyword(s):  
Tumor Angiogenesis ◽  
Topoisomerase I ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α

Silencing of Hypoxia Inducible Factor-1α by RNA Interference Attenuates Human Glioma Cell Growth In vivo

2007 ◽  
Vol 13 (8) ◽  
pp. 2441-2448 ◽  
Author(s):  
David L. Gillespie ◽  
Kum Whang ◽  
Brian T. Ragel ◽  
Jeannette R. Flynn ◽  
David A. Kelly ◽  
...  
Keyword(s):  
Rna Interference ◽  
Cell Growth ◽  
Glioma Cell ◽  
Hypoxia Inducible Factor ◽  
Human Glioma ◽  
Human Glioma Cell ◽  
Hypoxia Inducible Factor 1Α

Cellular and molecular mechanisms of hypoxia-inducible factor driven vascular remodeling

2007 ◽  
Vol 97 (05) ◽  
pp. 774-787 ◽  
Author(s):  
Norbert Weissmann ◽  
Friedrich Grimminger ◽  
Werner Seeger ◽  
Frank Rose ◽  
Jörg Hänze
Keyword(s):  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Ischemic Disease ◽  
Hypoxic Conditions ◽  
Concomitant Reduction ◽  
Adaptive Processes

SummaryHypoxia-inducible factor (HIF) is an oxygen-dependent transcription factor that activates a diverse set of target genes, the products of which are involved in adaptive processes to hypoxia. Employing genetic manipulation of HIF expression, in-vivo and cellular studies have focused on HIF as a crucial factor affecting hypoxia-induced vascular remodeling.Vascular remodeling comprises processes which establish and improve blood vessel supply such as vasculogenesis, angiogenesis and arteriogenesis. These processes are observed during ontogenesis, tumor progression, ischemic disease or physical training. Furthermore, under hypoxic conditions, a pulmonary-specific type of vascular remodeling called pulmonary arterial remodeling occurs that is characterized by thickening of the vessel wall with a concomitant reduction in the vessel lumen area, thereby limiting blood flow.This response results in pulmonary hypertension with right ventricular hypertrophy, a lethal disease. In this review, we summarize and discuss mechanisms by which HIF interferes with the different vascular remodeling processes.

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