Mechanistic Insights into the Events That Lead to Synergistic Induction of Interleukin 6 Transcription upon Activation of the Aryl Hydrocarbon Receptor and Inflammatory Signaling

DiNatale, Brett C.; Schroeder, Jennifer C.; Francey, Lauren J.; Kusnadi, Ann; Perdew, Gary H.

doi:10.1074/jbc.m110.118570

Cited by 99 publications

(84 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cAMP/PKA pathway induces IL-6 production in different cell types (36,37), and AhR activation is able to induce IL-6 production by de-repressing its promoter in tumor cell lines (23). Accordingly, our findings revealed a close relationship between AhR stimulation, cAMP, and cAMP-dependent IL-6 production.…”

Section: Discussionsupporting

confidence: 57%

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Sibilano

Frossi

Calvaruso

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.

show abstract

Section: Discussionsupporting

confidence: 57%

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Sibilano

Frossi

Calvaruso

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The AHR is a ligand-activated receptor that not only plays a role in mediating the toxicity of TCDD and related compounds but is also a potential target for the treatment of several diseases including autoimmune diseases, various inflammatory conditions, and cancer (McDougal et al, 2001;Quintana et al, 2008Quintana et al, , 2010Zhang et al, 2009Zhang et al, , 2012DiNatale et al, 2010bDiNatale et al, , 2011Murray et al, 2010;O'Donnell et al, 2010;Kiss et al, 2011;Li et al, 2011;Opitz et al, 2011;Singh et al, 2011). Depending on the tissue or cell, AHR agonists or antagonists may be required, and there is also evidence that the effects of various AHR-active compounds are structure-dependent.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

Jin

Lee

Safe

2012

J Pharmacol Exp Ther

105

View full text Add to dashboard Cite

Leflunomide, flutamide, nimodipine, mexiletine, sulindac, tranilast, 4-hydroxytamoxifen, and omeprazole are pharmaceuticals previously characterized as aryl hydrocarbon receptor (AHR) agonists in various cell lines and animal models. In this study, the eight AHR-active pharmaceuticals were investigated in highly aggressive aryl hydrocarbon (Ah)-responsive BT474 and MDA-MB-468 breast cancer cell lines, and their effects on AHR protein, CYP1A1 (protein and mRNA), CYP1B1 (mRNA), and cell migration were determined. 2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD) was used as a positive control. The AHR agonist activities of the pharmaceuticals depended on structure, response, and cell context. Most compounds induced one or more AHR-mediated responses in BT474 cells, whereas in Ah-responsive MDA-MB-468 cells effects of the AHR-active pharmaceuticals were highly variable. 4-Hydroxytamoxifen, mexiletine, and tranilast did not induce CYP1A1 in MDA-MB-468 cells; moreover, in combination with TCDD, mexiletine was a potent AHR antagonist, tranilast was a partial antagonist, and 4-hydroxytamoxifen also exhibited some AHR antagonist activity. Omeprazole and, to a lesser extent, sulindac and leflunomide were full and partial AHR agonists, respectively, in both breast cancer cell lines. These data indicate that the AHRactive pharmaceuticals are selective AHR modulators, and applications of these drugs for targeting the AHR must be confirmed by studies using the most relevant cell context.

show abstract

“…L-Kynurenine, kynurenic acid, and cinnabarinic acid are other endogenous molecules that are formed via catalytic breakdown of tryptophan. They can activate AhR signaling at levels that are physiologically or pathophysiologically relevant (DiNatale et al, 2010;Opitz et al, 2011;DeGroot and Denison, 2014;Lowe et al, 2014). Table 1 lists different types of small molecules and other factors that have been identified as AhR activators and ligands.…”

Section: The Realm Of Aryl Hydrocarbon Receptor Ligands: Agonists mentioning

confidence: 99%

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

2015

View full text Add to dashboard Cite

Mechanistic Insights into the Events That Lead to Synergistic Induction of Interleukin 6 Transcription upon Activation of the Aryl Hydrocarbon Receptor and Inflammatory Signaling

Cited by 99 publications

References 48 publications

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

Contact Info

Product

Resources

About