FICZ generates human tDCs that induce CD4+ CD25high Foxp3+ Treg-like cell differentiation

Jurado-Manzano, Brenda B.; Zavala-Reyes, Daniel; Turrubiartes-Martínez, Edgar; Portales-Pérez, Diana Patricia; González‐Amaro, Roberto; Layseca-Espinosa, Esther

doi:10.1016/j.imlet.2017.07.013

Cited by 24 publications

(22 citation statements)

References 56 publications

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“…Natural, AHR ligands, including AHR agonists, and selective AHR modulators (SARMs), have been suggested as potentially safe and effective therapeutic treatments that may be useful for the treatment of immune and inflammatory disease phenotypes that are regulated by AHR. However, it is crucial to first understand the exact molecular pathways that are impacted by each ligand across different tissues due to the possible toxic, carcinogenic, and teratogenic effects of AHR ligands [1,4,6,8,15,17,18,19,20,32,33,34,35,36,38,39,46,47,76,77,78,79]. Advances in nanotechnology may provide novel delivery methods that would permit highly tissue-specific targeting of AHR ligands that could avoid systemic AHR ligand exposure [14].…”

Section: Discussionmentioning

confidence: 99%

The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

Neavin

Liu

Ray

et al. 2018

IJMS

193

167

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The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

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Section: Discussionmentioning

confidence: 99%

The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

Neavin

Liu

Ray

et al. 2018

IJMS

193

167

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“…We observed that baicalein developed the secretion of TGF- β and suppressed the production of IL-6 in colitis mice. We considered that baicalein might affect the capability of DCs to produce IL-6 via AhR because AhR activation in DCs restrains the production of IL-6 [ 52 – 54 ]. But the specific relevance between baicalein and DCs during cytokine production should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Baicalein Restores the Balance of Th17/Treg Cells via Aryl Hydrocarbon Receptor to Attenuate Colitis

Liu

Chen

et al. 2020

Mediators of Inflammation

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As one of the ligands of aryl hydrocarbon receptor (AhR), baicalein, isolated from Scutellaria baicalensis Georgi, has been proved to exert potential therapeutic effects on ulcerative colitis (UC), but its therapeutic mechanism remains obscure. Authentically, ulcerative colitis can be alleviated by regulating the differentiation of naïve CD4+ T cells via AhR activation. So, our study planned to prove the hypothesis that baicalein protected mice against UC by regulating the balance of Th17/Treg cells via AhR activation. Immunofluorescence and western blot results showed that baicalein could promote AhR activation and induce it to transfer to the nucleus. We further determined the effect of baicalein on naïve CD4+ T cell differentiation in vitro by magnetic cell separation and drug intervention. The results showed that baicalein could promote Treg cell differentiation by activating AhR. In vivo study, UC mice were established by free drinking of dextran sulfate sodium (DSS) for 7 days and then were orally administrated by baicalein (10, 20, and 40 mg/kg), TCDD (AhR agonist), and CH223191 (antagonist). The results demonstrated that baicalein improved the symptoms of UC mice, regulated the balance of Th17/Treg cells, and restored the balance of proinflammatory cytokines such as IL-17, IL-6, and TNF-α; anti-inflammatory cytokines such as IL-10 and TGF-β; and epithelial protective cytokine IL-22 in UC mice, and these effects were related to AhR. Taken together, our research found that baicalein might be a potential drug for UC via regulating Treg cell differentiation and maintaining immune homeostasis and attempted to shed a light on the pivotal role of AhR in these effects.

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“…Activation of anti-inflammatory responses and tolerogenic cell phenotypes by FICZ, as well as TCDD, is now firmly established and several laboratories have detected induction of Foxp3-expressing Tregs by FICZ (Kimura et al 2008;Abu-Rezq and Millar 2013;Mohinta et al 2015;Jurado-Manzano et al 2017;Ye et al 2017;Ehrlich et al 2018). Such induction attenuated disease severity in murine models of diabetes and graft-versus host disease (Abu-Rezq and Millar 2013; Ehrlich et al 2018) ( Table 1).…”

Section: Differentiation Of Immune Cells and Immune Responsesmentioning

confidence: 99%

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

Rannug

2018

Critical Reviews in Toxicology

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The aryl hydrocarbon receptor (AHR) is not essential to survival, but does act as a key regulator of many normal physiological events. The role of this receptor in toxicological processes has been studied extensively, primarily employing the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, regulation of physiological responses by endogenous AHR ligands remains to be elucidated. Here, we review developments in this field, with a focus on 6-formylindolo[3,2-b]carbazole (FICZ), the endogenous ligand with the highest affinity to the receptor reported to date. The binding of FICZ to different isoforms of the AHR seems to be evolutionarily well conserved and there is a feedback loop that controls AHR activity through metabolic degradation of FICZ via the highly inducible cytochrome P450 1A1. Several investigations provide strong evidence that FICZ plays a critical role in normal physiological processes and can ameliorate immune diseases with remarkable efficiency. Low levels of FICZ are pro-inflammatory, providing resistance to pathogenic bacteria, stimulating the anti-tumor functions, and promoting the differentiation of cancer cells by repressing genes in cancer stem cells. In contrast, at high concentrations FICZ behaves in a manner similar to TCDD, exhibiting toxicity toward fish and bird embryos, immune suppression, and activation of cancer progression. The findings are indicative of a dual role for endogenously activated AHR in barrier tissues, aiding clearance of infections and suppressing immunity to terminate a vicious cycle that might otherwise lead to disease. There is not much support for the AHR ligand-specific immune responses proposed, the differences between FICZ and TCDD in this context appear to be explained by the rapid metabolism of FICZ.

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FICZ generates human tDCs that induce CD4+ CD25high Foxp3+ Treg-like cell differentiation

Cited by 24 publications

References 56 publications

The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

Baicalein Restores the Balance of Th17/Treg Cells via Aryl Hydrocarbon Receptor to Attenuate Colitis

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

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