Calcitriol Upregulates Open Chromatin and Elongation Markers at Functional Vitamin D Response Elements in the Distal Part of the 5-Lipoxygenase Gene

Stoffers, Kirsten L.; Sorg, B.; Seuter, Sabine; Rau, Oliver; Rådmark, Olof; Steinhilber, Dieter

doi:10.1016/j.jmb.2009.10.022

Cited by 16 publications

(18 citation statements)

References 37 publications

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“…This is agreement with previous analyses where the induction of immature 5-LO transcripts preceded the upregulation of mature 5-LO mRNA by both agents. We could recently show that induction of 5-LO mRNA expression by calcitriol and TGFβ is mainly due to the stimulation of transcript elongation [7]. Since correctly and alternatively spliced immature 5-LO transcripts are upregulated with similar time courses it seems that both agents do not affect the splicing process.…”

Section: Discussionmentioning

confidence: 99%

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Post-Transcriptional Regulation of 5-Lipoxygenase mRNA Expression via Alternative Splicing and Nonsense-Mediated mRNA Decay

et al. 2012

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5-Lipoxygenase (5-LO) catalyzes the two initial steps in the biosynthesis of leukotrienes (LT), a group of inflammatory lipid mediators derived from arachidonic acid. Here, we investigated the regulation of 5-LO mRNA expression by alternative splicing and nonsense-mediated mRNA decay (NMD). In the present study, we report the identification of 2 truncated transcripts and 4 novel 5-LO splice variants containing premature termination codons (PTC). The characterization of one of the splice variants, 5-LOΔ3, revealed that it is a target for NMD since knockdown of the NMD factors UPF1, UPF2 and UPF3b in the human monocytic cell line Mono Mac 6 (MM6) altered the expression of 5-LOΔ3 mRNA up to 2-fold in a cell differentiation-dependent manner suggesting that cell differentiation alters the composition or function of the NMD complex. In contrast, the mature 5-LO mRNA transcript was not affected by UPF knockdown. Thus, the data suggest that the coupling of alternative splicing and NMD is involved in the regulation of 5-LO gene expression.

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Section: Discussionmentioning

confidence: 99%

“…In the skin, Langerhans cells strongly express 5-LO [4]. During myeloid cell maturation, expression of 5-LO mRNA and protein is strongly upregulated by calcitriol and transforming growth factor-β (TGFβ) in a promoter-independent manner [5], [6], [7].…”

Section: Introductionmentioning

confidence: 99%

Post-Transcriptional Regulation of 5-Lipoxygenase mRNA Expression via Alternative Splicing and Nonsense-Mediated mRNA Decay

et al. 2012

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“…TGFβ and 1,25D may also cooperate to promote expression of other pathways linked to enhanced innate immune responses to infection such as induction of the enzyme 5-lipoxygenase (5-LO) that catalyzes synthesis of leukotrienes. Expression of 5-LO in human monocytes is induced by both 1,25D and TGFβ (Harle et al, 1998), with 1,25D enhancing expression of 5-LO through novel promoter-independent VDRE within exons 10 and 12 and intron M of the 5-LO gene (Stoffers et al, 2010). Although commonly associated with bronchial dilation and asthma, leukotrienes are also known to participate in leukocyte accumulation at sites of infection and phagocytosis of bacteria (Peters-Golden et al, 2005).…”

Section: Antibacterial Responses To Vitamin Dmentioning

confidence: 99%

Impact of vitamin D on immune function: lessons learned from genome-wide analysis

et al. 2014

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Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans.

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“…Additionally, this effect was strongly enhanced by the combination of 1α,25(OH) 2 D 3 with transforming growth factor β (TGF-β) (Brungs et al, 1995; Harle et al, 1998). Mechanistically, the effect of 1α,25(OH) 2 D 3 on 5-LO expression was related to VDR binding sites in the 5-LO promoter and distal parts of the 5-LO gene (Sorg et al, 2006; Stoffers et al, 2010) and is due to stimulation of 5-LO transcript elongation (Stoffers et al, 2010). …”

Section: Regulation Of the Expression Of Proinflammatory Enzymes By 1mentioning

confidence: 99%

Vitamin D in inflammatory diseases

2014

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Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq.

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Calcitriol Upregulates Open Chromatin and Elongation Markers at Functional Vitamin D Response Elements in the Distal Part of the 5-Lipoxygenase Gene

Cited by 16 publications

References 37 publications

Post-Transcriptional Regulation of 5-Lipoxygenase mRNA Expression via Alternative Splicing and Nonsense-Mediated mRNA Decay

Post-Transcriptional Regulation of 5-Lipoxygenase mRNA Expression via Alternative Splicing and Nonsense-Mediated mRNA Decay

Impact of vitamin D on immune function: lessons learned from genome-wide analysis

Vitamin D in inflammatory diseases

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