Novel Compound 2-Methyl-2<i>H</i>-pyrazole-3-carboxylic Acid (2-methyl-4-<i>o</i>-tolylazo-phenyl)-amide (CH-223191) Prevents 2,3,7,8-TCDD-Induced Toxicity by Antagonizing the Aryl Hydrocarbon Receptor

Kim, Sun‐Hee; Henry, Ellen C.; Kim, Dong Kyu; Kim, Yun-Hee; Shin, Kum Joo; Han, Myoung Sook; Lee, Taehoon G.; Kang, Jongku; Gasiewicz, Thomas A.; Ryu, Sung Ho; Suh, Pann‐Ghill

doi:10.1124/mol.105.021832

Cited by 234 publications

(175 citation statements)

References 29 publications

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“…3A). Furthermore, the specific AHR antagonist CH-223191 [34] completely reversed the inhibitory activity of TCDD on IL-17A as well as the enhancing activity on IL-22 ( Fig. 3B).…”

Section: Involvement Of Ahr In Upregulation Of Il-22 and Downregulatimentioning

confidence: 82%

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Ramirez¹,

Brembilla²,

Sorg³

et al. 2010

Eur J Immunol

158

140

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Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo [3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-c, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4 1 T cells. The specific AHRinhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4 1 T cells to produce IL-22 without IL-17 and IFN-c. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161 1 Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4 1 T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. IntroductionLocal cytokine milieu during antigen presentation profoundly affects the differentiation program of CD4 1 T cells [1]. In the mouse, TGF-b, in the presence of IL-6 and pro-inflammatory cytokines, favors the emergence of Th17 cells that produce IL-17 and express the master transcription factor retinoic acid-related orphan receptor (ROR)gt [2][3][4][5][6]. Th17 cells are expanded and terminally differentiated in the presence of . Human Th17 cells may be generated in the presence of IL-1 and IL-23; IL-1 and IL-6; or . Th17 cells express CCR6 and 2450produce the CCR6-ligand CCL20, thereby amplifying Th17 cell recruitment at sites of inflammation [11]. IL-22, a member of the IL-10-family, is produced by Th17 cells, and to some extent by Th1 cells, NKT cells, NK cells and lymphoid tissue inducer-like cells [12]. IL-22 signals via a receptor consisting of IL-22R and IL-10R2 subunits [11]. Cells of hemapoietic origin do not express IL-22R; instead, IL-2R is highly expressed by epithelial cells of the gastrointestinal tract and the skin. In the mouse, IL-23 was shown to drive preferential expansion of cells that co-express IL-22 and IL-17, that may synergize to augment the expression of genes involved in defense against microbial pathogens [13,14]. However, several mouse models of infection and autoimmunity suggested distinct roles for .In addition to cytokines, other mediators may impact CD4 1 T-cell differentiation. We and others have shown that prostaglandin E2 (PGE2) favors human Th17 expansion [20][21][22]. Furthermore, ligands of the aryl hydrocarbon receptor (AHR) exert a role. AHR is a...

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“…3A). Furthermore, the specific AHR antagonist CH-223191 [34] completely reversed the inhibitory activity of TCDD on IL-17A as well as the enhancing activity on IL-22 ( Fig. 3B).…”

Section: Involvement Of Ahr In Upregulation Of Il-22 and Downregulatimentioning

confidence: 82%

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Ramirez¹,

Brembilla²,

Sorg³

et al. 2010

Eur J Immunol

158

140

View full text Add to dashboard Cite

show abstract

“…After transient transfection with the artificial CYP1A1 reporter construct pT81/3 Â DRE, the cells were treated with 10 mm CH-223191, an AhR receptor antagonist, which potently inhibits TCDDinduced AhR-dependent transcription and blocks the binding of TCDD to AhR (Kim et al, 2006). CH-223191 decreased DRE reporter activity of all respective glioma cell lines at 10 mM (Figure 2a).…”

Section: Pharmacological and Genetic Modulation Of Ahr Activity In Glmentioning

confidence: 99%

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

Pantazis²,

et al. 2009

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“…HPs were then subjected to 3 different growth conditions to assess the activity of AhR in this cell population: (1) the steady-state condition consisting of cells maintained in 0.2 mM of FICZ; (2) exposure to an increased FICZ concentration to 0.4 mM; or (3) growth in 0.2 mM of FICZ but also in the presence of 5 mM of a known AhR inhibitor, CH223191. 40 In contrast to the mockinfected HPs, the AhR-driven reporter-infected HPs displayed a modest increase in dsRed expression, suggesting that the AhRresponsive elements in the reporter were being transactivated in the HPs ( Figure 4B). An increase in the FICZ concentration to 0.4 mM significantly increased DsRed expression ( Figure 4B).…”

Section: Ahr Mediates the Expansion And Specification Of Hpsmentioning

confidence: 99%

The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation

Smith

Rozelle

Leung

et al. 2013

Blood

125

123

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Novel Compound 2-Methyl-2H-pyrazole-3-carboxylic Acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) Prevents 2,3,7,8-TCDD-Induced Toxicity by Antagonizing the Aryl Hydrocarbon Receptor

Cited by 234 publications

References 29 publications

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation

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