Mucosal inflammation downregulates PHD1 expression promoting a barrier‐protective HIF‐1α response in ulcerative colitis patients

Brown, Eric J.; Rowan, Catherine; Strowitzki, Moritz J.; Fagundes, Raphael R.; Faber, Klaas Nico; Güntsch, Annemarie; Halligan, Doug N.; Kugler, Julia; Jones, F. G.; Lee, Chee Teik; Doherty, Glen; Taylor, Cormac T.

doi:10.1096/fj.201902103r

Cited by 20 publications

(19 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Relevance to IBD is suggested by studies in experimental colitis models ( Sun et al, 2019 ; Colgan et al, 2020 ; Yin et al, 2020 ), and cell lines ( Muenchau et al, 2019 ; Vissenaekens et al, 2019 ), which indicate a protective stabilization of HIF1α, attenuating mucosal inflammation and promoting barrier formation. Moreover, reagents that activate HIF via inhibition of the prolyl hydroxylase enzymes, are suggested to induce hypoxia-mediated resolution in patients with intestinal mucosal inflammatory disease ( Glover and Colgan, 2011 ; Brown et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Patient Derived Colonoids as Drug Testing Platforms–Critical Importance of Oxygen Concentration

et al. 2021

View full text Add to dashboard Cite

Treatment of inflammatory bowel disease (IBD) is challenging, with a series of available drugs each helping only a fraction of patients. Patients may face time-consuming drug trials while the disease is active, thus there is an unmet need for biomarkers and assays to predict drug effect. It is well known that the intestinal epithelium is an important factor in disease pathogenesis, exhibiting physical, biochemical and immunologic driven barrier dysfunctions. One promising test system to study effects of existing or emerging IBD treatments targeting intestinal epithelial cells (IECs) is intestinal organoids (“mini-guts”). However, the fact that healthy intestinal epithelium is in a physiologically hypoxic state has largely been neglected, and studies with intestinal organoids are mainly performed at oxygen concentration of 20%. We hypothesized that lowering the incubator oxygen level from 20% to 2% would recapitulate better the in vivo physiological environment of colonic epithelial cells and enhance the translational value of intestinal organoids as a drug testing platform. In the present study we examine the effects of the key IBD cytokines and drug targets TNF/IL17 on human colonic organoids (colonoids) under atmospheric (20%) or reduced (2%) O2. We show that colonoids derived from both healthy controls and IBD-patients are viable and responsive to IBD-relevant cytokines at 2% oxygen. Because chemokine release is one of the important immunoregulatory traits of the epithelium that may be fine-tuned by IBD-drugs, we also examined chemokine expression and release at different oxygen concentrations. We show that chemokine responses to TNF/IL17 in organoids display similarities to inflamed epithelium in IBD-patients. However, inflammation-associated genes induced by TNF/IL17 were attenuated at low oxygen concentration. We detected substantial oxygen-dependent differences in gene expression in untreated as well as TNF/IL17 treated colonoids in all donors. Further, for some of the IBD-relevant cytokines differences between colonoids from healthy controls and IBD patients were more pronounced in 2% O2 than 20% O2. Our results strongly indicate that an oxygen concentration similar to the in vivo epithelial cell environment is of essence in experimental pharmacology.

show abstract

Section: Discussionmentioning

confidence: 99%

Patient Derived Colonoids as Drug Testing Platforms–Critical Importance of Oxygen Concentration

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The presence of hypoxia restricted to the epithelial surface in animal models of IBD has been observed by using 2-nitroimidazole dyes [ 11 ]. Using endoscopic oximetry, prominent levels of mucosal hypoxia correlated with the degree of inflammation were found in ulcerative colitis (UC) patients [ 12 ]. Contributors to tissue hypoxia in inflamed tissues include increased oxygen consumption by infiltrating immune cells which utilize O 2 to sustain synthesis of inflammatory cytokines and mediators, as well as impaired oxygen supply to these tissues caused by vascular damage, thrombosis, and edema [ 13 ].…”

Section: Hypoxia and Inflammationmentioning

confidence: 99%

“…However, TNF-α treatment reduced HIF-1α protein expression in skeletal muscle myocytes under normoxic conditions [ 63 ]. It was recently shown that under normoxic conditions stimulation of human intestinal epithelial Caco-2 cells with pro-inflammatory cytokines including TNF-α downregulated PHD1 mRNA levels which were correlated with decreased CCAAT-enhancer binding protein (C/EBPα) mRNA and protein expression, suggesting that the effect of TNF-α on the C/EBPα/PHD1 mechanism could lead to increased HIF-1α stabilization in the mucosal tissue of UC patients [ 12 ]. TNF-α treatment also significantly upregulates HIF-1α protein and mRNA levels in human squamous lung A549 and H226 cells, which inhibits A549 cell proliferation and adhesion as well as TNF-α-activated transcriptional activity of HIF-1α, resulting in suppression of vasodilator-stimulated phosphoprotein (VASP) and consequent inhibition of transplanted tumors growth in nude mice [ 64 ].…”

Section: Regulation Of Hif By Cytokinesmentioning

confidence: 99%

Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

Malkov

Lee

Taylor

2021

Cells

Self Cite

View full text Add to dashboard Cite

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 hypoxic sites.

show abstract

“…CCL2 and CXCL8 belong to a family of chemokines, which are mainly involved in immunoregulatory and inflammatory processes [ 43 ]. HIF1A acts as a master regulator of cellular and systemic homeostatic responses to hypoxia and has a regulatory role in intestinal mucosal inflammation in UC patients [ 44 ]. For JUN, it has been confirmed to improve gastrointestinal mucosal conditions in UC patients by modulating JUN-related pathways [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Exploration of the Potential Mechanisms of Wumei Pill for the Treatment of Ulcerative Colitis by Network Pharmacology

Huang

Zheng

et al. 2021

Gastroenterology Research and Practice

View full text Add to dashboard Cite

Background. Wumei pill (WMP) has a long history of colitis treatment in China, but the protective mechanisms have not been elucidated. To uncover the potential mechanisms of WMP against ulcerative colitis (UC), the network pharmacology approach was utilized in this study. Methods. Public databases were utilized to identify the potential targets of WMP and genes related to UC. Based on the identified overlapping common targets, drug-ingredient-target gene network, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) analysis were conducted. Molecular docking was carried out to verify the selected key active ingredients and core targets. Results. 129 active ingredients and 622 target genes were obtained. The drug-ingredient-target gene network revealed 52 active ingredients of WMP acting on 73 targets related to UC. GO analysis revealed that biological processes were mainly associated with oxidative stress, such as, reactive oxygen species metabolic processes, response to oxidative stress, cellular response to oxidative stress, response to reactive oxygen species, and regulation of reactive oxygen species metabolic processes. KEGG analysis revealed that the immune- and inflammation-related pathways, tumor-related signaling pathways, and microbial infection-related signaling pathways were the most significant. PPI network identified 13 core target genes. The molecular docking results indicated the formation of stable bonds between the active ingredients and core target genes. Conclusions. The approach of network pharmacology reveals the key ingredients, potential core targets, and biological process of WMP in the treatment of UC. The mechanisms of action of WMP involve anti-inflammation, antioxidation, and modulation of immunity, which provides evidence for the therapeutic role of WMP in UC.

show abstract

Mucosal inflammation downregulates PHD1 expression promoting a barrier‐protective HIF‐1α response in ulcerative colitis patients

Cited by 20 publications

References 33 publications

Patient Derived Colonoids as Drug Testing Platforms–Critical Importance of Oxygen Concentration

Patient Derived Colonoids as Drug Testing Platforms–Critical Importance of Oxygen Concentration

Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

Exploration of the Potential Mechanisms of Wumei Pill for the Treatment of Ulcerative Colitis by Network Pharmacology

Contact Info

Product

Resources

About