NF-?B links innate immunity to the hypoxic response through transcriptional regulation of HIF-1a (original) (raw)
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The Journal of Immunology, 2011
Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-kB. Recent studies have revealed a high degree of interdependence between HIF and NF-kB signaling; however, the relative contribution of each to hypoxiainduced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-kB to demonstrate that hypoxia activates NF-kB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-kB, we confirm a unidirectional dependence of hypoxic HIF-1a accumulation upon an intact canonical NF-kB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-kB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-kB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1a and the p65 subunit of NF-kB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-kB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.
Regulation of hypoxia-inducible factor-1α by NF-κB
Biochemical Journal, 2008
HIF (hypoxia-inducible factor) is the main transcription factor activated by low oxygen tensions. HIF-1α (and other α subunits) is tightly controlled mostly at the protein level, through the concerted action of a class of enzymes called PHDs (prolyl hydroxylases) 1, 2 and 3. Most of the knowledge of HIF derives from studies following hypoxic stress; however, HIF-1α stabilization is also found in non-hypoxic conditions through an unknown mechanism. In the present study, we demonstrate that NF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression. The HIF-1α promoter is responsive to selective NF-κB subunits. siRNA (small interfering RNA) studies for individual NF-κB members revealed differential effects on HIF-1α mRNA levels, indicating that NF-κB can regulate basal HIF-1α expression. Finally, when endogenous NF-κB is induced by TNFα (tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner. In conclusion, we find that NF-κB can regulate...
The Role of NF-κB in Hypoxia-Induced Gene Expression
Annals of the New York Academy of Sciences, 2009
Hypoxia is a common physiologic and pathophysiologic stimulus that activates the expression of genes through oxygen-sensitive transcription factors including the hypoxiainducible factor (HIF) and nuclear factor-kappaB (NF-κB). Hypoxia-dependent gene expression can have important physiologic or pathophysiologic consequences for an organism, depending upon the cause of the hypoxic insult. Consequently, this pathway represents an attractive therapeutic target in a number of disease states. While the mechanism linking hypoxia to the activation of HIF has been extensively studied, our understanding of how hypoxia activates NF-κB is limited. Recent studies have demonstrated that similar oxygen-sensing mechanisms are employed in conferring oxygen sensitivity to both HIF and NF-κB−dependent gene expression. Furthermore, there is an extensive degree of cross-talk occurring between NF-κB and HIF. Investigations into mechanisms of hypoxic activation of HIF and NF-κB and how these signaling pathways interact will uncover new therapeutic modalities in a diverse range of disease states where hypoxia is a feature of the microenvironment including cancer, vascular disease, and chronic inflammation.
The Journal of Immunology, 2010
Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptio...
Regulation of gene expression by oxygen: NF-κB and HIF-1, two extremes
Free Radical Biology and Medicine, 2002
Aerobic life is dependent on molecular oxygen for ATP regeneration, but only possible in a narrow range of oxygen concentrations. Increased oxygen tension is toxic through the generation of reactive oxygen species (ROS), while a decrease in oxygen concentration impairs energy availability and, hence, cell viability. Cells have developed strategies to respond to changes in oxygen tension: specific systems detect excessive ROS and hypoxia, leading to the activation of specific transcription factors and expression of appropriate target genes. The aim of this review is to describe how hypoxia-inducible factor-1 (HIF-1) and nuclear factor-B (NF-B) are regulated and what could be the sensors to the changes in oxygen levels. Some of the physiological responses initiated by these transcription factors are also mentioned.
Hypoxia. Regulation of NFκB signalling during inflammation: the role of hydroxylases
Arthritis Research & Therapy, 2009
NFκB is a master regulator of innate immunity and inflammatory signalling. Microenvironmental hypoxia has long been identified as being coincident with chronic inflammation. The contribution of microenvironmental hypoxia to NFκB-induced inflammation has more recently been appreciated. Identification of the co-regulation of NFκB and hypoxia inducible factor (HIF) pathways by 2-oxoglutarate-dependent hydroxylase family members has highlighted an intimate relationship between NFκB inflammatory signalling and HIF-mediated hypoxic signalling pathways. Adding another layer of complexity to our understanding of the role of NFκB inflammatory signalling by hypoxia is the recent recognition of the contribution of basal NFκB activity to HIF-1α transcription. This observation implicates an important and previously unappreciated role for NFκB in inflammatory disease where HIF-1α is activated. The present review will discuss recent literature pertaining to the regulation of NFκB inflammatory signalling by hypoxia and some of the inflammatory diseases where this may play an important role. Furthermore, we will discuss the potential for prolyl-hydroxylase inhibitors in inflammatory disease.
Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines
Cells, 2021
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hy...
Cells, 2016
As Nuclear Factor-κB (NF-κB) is a major transcription factor responding to cellular stress, it is perhaps not surprising that is activated by hypoxia, or decreased oxygen availability. However, how NF-κB becomes activated in hypoxia is still not completely understood. Several mechanisms have been proposed and this review will focus on the main findings highlighting the molecules that have been identified in the process of hypoxia induced NF-κB. In addition, we will discuss the role of NF-κB in the control of the cellular response to hypoxia.