Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proceedings of the National Academy of Sciences of the United States of America

Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2006; 103(48):18154-9. DOI: 10.1073/pnas.0602235103
Source: PubMed


Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NFkappaB is activated in hypoxia, an event that has significant implications for tumor progression. Here, we demonstrate that hypoxia activates NFkappaB through a pathway involving activation of IkappaB kinase-beta (IKKbeta) leading to phosphorylation-dependent degradation of IkappaBalpha and liberation of NFkappaB. Furthermore, through increasing the pool and/or activation potential of IKKbeta, hypoxia amplifies cellular sensitivity to stimulation with TNFalpha. Within its activation loop, IKKbeta contains an evolutionarily conserved LxxLAP consensus motif for hydroxylation by prolyl hydroxylases (PHDs). Mimicking hypoxia by treatment of cells with siRNA against PHD-1 or PHD-2 or the pan-prolyl hydroxylase inhibitor DMOG results in NFkappaB activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NFkappaB reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NFkappaB. Hypoxia increases both the expression and activity of IKKbeta, and site-directed mutagenesis of the proline residue (P191A) of the putative IKKbeta hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NFkappaB activity through decreased PHD-dependent hydroxylation of IKKbeta, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways.

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Available from: Paul N Moynagh, Oct 02, 2015
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    • "Indeed, the relationship between the hypoxic and inflammatory responses is tightly controlled (Figure 2A). As noted above, hypoxia and bacterial infections result in increased nuclear factor-kappa B (NF-kB) activity in phagocytes, which in turn induces HIF-1a mRNA transcription (Cummins et al., 2006; Fitzpatrick et al., 2011; Rius et al., 2008). Together with NF-kB, the p42/ p44 mitogen-activated protein kinase (MAPK) (Erk) pathway is involved in LPS-induced HIF-1a induction in human monocytes (Frede et al., 2006). "
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    ABSTRACT: The hypoxic response in cells and tissues is mediated by the family of hypoxia-inducible factor (HIF) transcription factors; these play an integral role in the metabolic changes that drive cellular adaptation to low oxygen availability. HIF expression and stabilization in immune cells can be triggered by hypoxia, but also by other factors associated with pathological stress: e.g., inflammation, infectious microorganisms, and cancer. HIF induces a number of aspects of host immune function, from boosting phagocyte microbicidal capacity to driving T cell differentiation and cytotoxic activity. Cellular metabolism is emerging as a key regulator of immunity, and it constitutes another layer of fine-tuned immune control by HIF that can dictate myeloid cell and lymphocyte development, fate, and function. Here we discuss how oxygen sensing in the immune microenvironment shapes immunological response and examine how HIF and the hypoxia pathway control innate and adaptive immunity.
    Immunity 10/2014; 41(4):518-528. DOI:10.1016/j.immuni.2014.09.008 · 21.56 Impact Factor
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    • "Under normal conditions, HIF activity is rendered inactive by prolyl hydroxylases (PHD) and factor inhibiting HIF (FIH). Both PHD and FIH prevent the activation of IκB kinase B and hence inhibit NF-κB activation [23–27]. "
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    ABSTRACT: Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation.
    International Journal of Endocrinology 04/2014; 2014(6):451035. DOI:10.1155/2014/451035 · 1.95 Impact Factor
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    • "There is a tight interconnection between the NFκB and HIF-1α (hypoxia-inducible factor 1-α) signaling pathways in the regulation of inflammatory host responses (Barnes, 1997; Taylor, 2008). Thus, NFκB is activated under hypoxia (Cummins et al., 2006) but in turn also induces transcriptional up-regulation of HIF-1α expression (Rius et al., 2008). NFκB activation and subsequent pro-inflammatory gene expression is supposed to be abrogated by an enhanced expression of IκB kinase-α (IKKα) under prolonged hypoxia (Lawrence et al., 2005; Cummins et al., 2006). "
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    ABSTRACT: Genital tract infections with Chlamydia trachomatis (C. trachomatis) are the most frequent sexually transmitted disease worldwide. Severe clinical sequelae such as pelvic inflammatory disease (PID), tubal occlusion, and tubal infertility are linked to inflammatory processes of chronically infected tissues. The oxygen concentrations in the female urogenital tract are physiologically low and further diminished (0.5-5% O2, hypoxia) during an ongoing inflammation. However, little is known about the effect of a low oxygen environment on genital C. trachomatis infections. In this study, we investigated the host immune responses during reactivation of IFN-γ induced persistent C. trachomatis infection under hypoxia. For this purpose, the activation of the MAP-kinases p44/42 and p38 as well as the induction of the pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 were analyzed. Upon hypoxic reactivation of IFN-γ induced persistent C. trachomatis infection, the phosphorylation of the p44/42 but not of the p38 MAP-kinase was significantly diminished compared to IFN-γ induced chlamydial persistence under normoxic condition. In addition, significantly reduced IL-6 and IL-8 mRNA expression levels were observed for reactivated Chlamydiae under hypoxia compared to a persistent chlamydial infection under normoxia. Our findings indicate that hypoxia not only reactivates IFN-γ induced persistent C. trachomatis infections resulting in increased bacterial growth and progeny but also dampens inflammatory host immune signaling responses that are normally observed in a normoxic environment.
    Frontiers in Cellular and Infection Microbiology 04/2014; 4:43. DOI:10.3389/fcimb.2014.00043 · 3.72 Impact Factor
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