Transcription Factor HIF-1α Controls Expression of the Cytokine IL-22 in CD4 T Cells

Budda, Scott A; Girton, Alanson; Henderson, Jacob G.; Zenewicz, Lauren A.

doi:10.4049/jimmunol.1600250

Cited by 33 publications

(23 citation statements)

References 28 publications

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“…In addition, the novel finding that IL-22 is a transcriptional target for HIF may indicate that hypoxia and hypoxiaresponses are globally important in regulating mucosal cytokine responses 39 Given that IL-22 has a dual nature in promoting both inflammation and resolution, contextually coupling both IL-12p40 and IL-22 to a hypoxia response would support the hypothesis that HIF signaling acts to limit the extent of the immune response. Future studies identifying contrasting regulation of HIF/IL-12/23 responses in innate vs. adaptive cells, are likely to be important.…”

Section: Discussionmentioning

confidence: 99%

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation

et al. 2017

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Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40 murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

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Section: Discussionmentioning

confidence: 99%

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation

et al. 2017

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“…The role of HIF1α in inducing cytokine production has been shown in a few reports, such as that of Jeong et al [50] whereby HIF1α inhibition abrogated the deferoxamine-induced cytokine production (IL6, IL8 and TNFα) in human mast cells, HMC-1 cells. Further, Budda et al [51] demonstrated that HIF-1α controlled IL-22 expression in CD4 T Cells under hypoxia. However, the exact mechanism by which HIF1α controls the production of these inflammatory mediators was not completely understood.…”

Section: Discussionmentioning

confidence: 99%

HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes

Ali

Phillips

Mahmoud

2020

Cells

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Obesity is associated with the accumulation of dysfunctional adipose tissue that secretes several pro-inflammatory cytokines (adipocytokines). Recent studies have presented evidence that adipose tissues in obese individuals and animal models are hypoxic, which may result in upregulation and stabilization of the hypoxia inducible factor HIF1α. Epigenetic mechanisms such as DNA methylation enable the body to respond to microenvironmental changes such as hypoxia and may represent a mechanistic link between obesity-associated hypoxia and upregulated inflammatory adipocytokines. The purpose of this study was to investigate the role of hypoxia in modifying adipocytokine DNA methylation and subsequently adipocytokine expression. We suggested that this mechanism is mediated via the DNA demethylase, ten-eleven translocation-1 (TET1), transcription of which has been shown to be induced by HIF1α. To this end, we studied the effect of hypoxia (2% O2) in differentiated subcutaneous human adipocytes in the presence or absence of HIF1α stabilizer (Dimethyloxalylglycine (DMOG), 500 μM), HIF1α inhibitor (methyl 3-[[2-[4-(2-adamantyl) phenoxy] acetyl] amino]-4-hydroxybenzoate, 30 μM), or TET1-specific siRNA. Subjecting the adipocytes to hypoxia significantly induced HIF1α and TET1 protein levels. Moreover, hypoxia induced global hydroxymethylation, reduced adipocytokine DNA promoter methylation, and induced adipocytokine expression. These effects were abolished by either HIF1α inhibitor or TET1 gene silencing. The major hypoxia-responsive adipocytokines were leptin, interleukin-1 (IL6), IL1β, tumor necrosis factor α (TNFα), and interferon γ (IFNγ). Overall, these data demonstrate an activation of the hydroxymethylation pathway mediated by TET1. This pathway contributes to promoter hypomethylation and gene upregulation of the inflammatory adipocytokines in adipocytes in response to hypoxia.

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“…An in vitro study showed that in vitro infection with influenza H1N1 virus promotes the secretion of proinflammatory cytokines by inducing nuclear translocation of HIF‐1α (Guo et al., ). HIF‐1α appears to control expression of IL‐22 in CD4 T cells (Budda, Girton, Henderson, & Zenewicz, ). It is also important to stress that changes in secretion of cytokines and chemokines by astrocytes in this study were induced in the absence of any other cells of the NVU from the cultures; this finding is significant because it has been shown previously that tumor necrosis factor like weak inducer of apoptosis is secreted mainly by neurons during CI and binds to Fn14 on astrocytes, leading to proinflammatory molecule production (Saas et al., ).…”

Section: Discussionmentioning

confidence: 99%

Rat astrocytes during anoxia: Secretome profile of cytokines and chemokines

et al. 2018

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IntroductionThe precise mechanisms of the inflammatory responses after cerebral ischemia in vivo are difficult to elucidate because of the complex nature of multiple series of interactions between cells and molecules. This study explored temporal patterns of secretion of 30 cytokines and chemokines from Sprague Dawley rat astrocytes in primary culture in order to elucidate signaling pathways that are triggered by astrocytes during anoxia.MethodsPrimary cultures of rat brain astrocytes were incubated for periods of 2–24 hr in the absence of oxygen (anoxia) or under normal partial pressure of oxygen (controls). Simultaneous detection of 29 cytokines and chemokines in the samples was performed using a rat cytokine array panel, while the temporal pattern of angiopoietin‐1 (Ang‐1) secretion was determined separately using ELISA. Wilcoxon–Mann–Whitney test was used to compare normoxic and anoxic samples and the Hodge–Lehman estimator with exact 95% confidence intervals was computed to assess the size of differences in cytokine secretion. The obtained data were imported into the Core Analysis tool of Ingenuity Pathways Analysis software in order to relate changes in secretion of cytokines and chemokines from astrocytes during anoxia to potential molecular signal networks.ResultsWith the exception of Ang‐1, concentrations of all cytokines/chemokines in samples collected after anoxia exposure were either the same, or higher, than in control groups. No clear pattern of changes could be established for groups of cytokines with similar effects (i.e., pro‐ or anti‐inflammatory cytokines). The pattern of changes in cytokine secretion during anoxia was associated with the HIF‐1α‐mediated response, as well as cytokines IL‐1β and cathepsin S pathways, which are related to initiation of inflammation and antigen presentation, respectively, and to ciliary neurotrophic factor.ConclusionsThese in vitro findings suggest that astrocytes may play a role in triggering inflammation during anoxia/ischemia of the brain.

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Transcription Factor HIF-1α Controls Expression of the Cytokine IL-22 in CD4 T Cells

Cited by 33 publications

References 28 publications

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation

HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes

Rat astrocytes during anoxia: Secretome profile of cytokines and chemokines

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