Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated receptor that regulates the metabolism of several xenobiotics and participates in ocular inflammation. Although severe inflammation is a major risk of retinal damage, the underlying mechanism is not well established. In this study, to elucidate how AHR mediates inflammation homeostasis, we hypothesized that AHR expression may diminish during long-term exposure to benzo [a] pyrene (B [a]P), a carcinogen in cigarette smoke. The blockage of AHR function considerably impaired suppressor of cytokine signaling 3 (SOCS3) negative feedback regulation and upregulated B [a]P-induced pro-inflammation. Signal transducer and activator of transcription 3 (STAT3) was activated by B [a] P due to AHR dysfunction in human adult retinal pigment epithelial cells (ARPE-19). The STAT3-inducible element revealed higher activity in AHR knockout cells with B [a] P treatment, but not in wild type ARPE-19 cells. Moreover, AHR dysfunction led to STAT3 hypo-ubiquitination and changed the STAT3–SOCS3 interaction. Increased STAT3–SOCS3 complex during AHR dysfunction by B [a] P was suppressed by nifuroxazide in ARPE-19 cells. Furthermore, the in vivo results showed that STAT3 inhibition during AHR impairment by long-term B [a] P exposure preserved the retina thickness and reversed the visual function in male C57Bl/6 mice. Overall, long-term B [a] P exposure may attenuate AHR function, dysregulating the homeostasis of the SOCS3–STAT3 axis with intensive STAT3 activation. This finding is significant given that the disintegration of the AHR–SOCS3 axis is a sensitive factor involved in AMD-like lesion development in the retina, revealing that the low AHR level may be associated with cigarette smoking or xenobiotics exposure, causing retina inflammation and damage.

Original languageEnglish
JournalCell Biology and Toxicology
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Aryl Hydrocarbon Receptors
STAT3 Transcription Factor
Carcinogens
Down-Regulation
Cytokines
Inflammation
Retina
Benzo(a)pyrene
Xenobiotics
Tobacco Products
Homeostasis
Retinal Pigments
Disintegration
Ubiquitination
Metabolism
Smoke
Transcriptional Activation
Smoking
Epithelial Cells
Chemical activation

Keywords

  • Aryl hydrocarbon receptor
  • Benzo [a] pyrene
  • Retinal degeneration
  • SOCS3
  • STAT3

ASJC Scopus subject areas

  • Toxicology
  • Cell Biology
  • Health, Toxicology and Mutagenesis

Cite this

@article{e46e19dcec0d4445a35a41a8b10befe8,
title = "Down-regulation of aryl hydrocarbon receptor intensifies carcinogen-induced retinal lesion via SOCS3-STAT3 signaling",
abstract = "The aryl hydrocarbon receptor (AHR) is a ligand-activated receptor that regulates the metabolism of several xenobiotics and participates in ocular inflammation. Although severe inflammation is a major risk of retinal damage, the underlying mechanism is not well established. In this study, to elucidate how AHR mediates inflammation homeostasis, we hypothesized that AHR expression may diminish during long-term exposure to benzo [a] pyrene (B [a]P), a carcinogen in cigarette smoke. The blockage of AHR function considerably impaired suppressor of cytokine signaling 3 (SOCS3) negative feedback regulation and upregulated B [a]P-induced pro-inflammation. Signal transducer and activator of transcription 3 (STAT3) was activated by B [a] P due to AHR dysfunction in human adult retinal pigment epithelial cells (ARPE-19). The STAT3-inducible element revealed higher activity in AHR knockout cells with B [a] P treatment, but not in wild type ARPE-19 cells. Moreover, AHR dysfunction led to STAT3 hypo-ubiquitination and changed the STAT3–SOCS3 interaction. Increased STAT3–SOCS3 complex during AHR dysfunction by B [a] P was suppressed by nifuroxazide in ARPE-19 cells. Furthermore, the in vivo results showed that STAT3 inhibition during AHR impairment by long-term B [a] P exposure preserved the retina thickness and reversed the visual function in male C57Bl/6 mice. Overall, long-term B [a] P exposure may attenuate AHR function, dysregulating the homeostasis of the SOCS3–STAT3 axis with intensive STAT3 activation. This finding is significant given that the disintegration of the AHR–SOCS3 axis is a sensitive factor involved in AMD-like lesion development in the retina, revealing that the low AHR level may be associated with cigarette smoking or xenobiotics exposure, causing retina inflammation and damage.",
keywords = "Aryl hydrocarbon receptor, Benzo [a] pyrene, Retinal degeneration, SOCS3, STAT3",
author = "Tsai, {Chi Hao} and Yi Lee and Li, {Ching Hao} and Cheng, {Yu Wen} and Kang, {Jaw Jou}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s10565-019-09499-z",
language = "English",
journal = "Cell Biology and Toxicology",
issn = "0742-2091",
publisher = "Springer Netherlands",

}

TY - JOUR

T1 - Down-regulation of aryl hydrocarbon receptor intensifies carcinogen-induced retinal lesion via SOCS3-STAT3 signaling

AU - Tsai, Chi Hao

AU - Lee, Yi

AU - Li, Ching Hao

AU - Cheng, Yu Wen

AU - Kang, Jaw Jou

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The aryl hydrocarbon receptor (AHR) is a ligand-activated receptor that regulates the metabolism of several xenobiotics and participates in ocular inflammation. Although severe inflammation is a major risk of retinal damage, the underlying mechanism is not well established. In this study, to elucidate how AHR mediates inflammation homeostasis, we hypothesized that AHR expression may diminish during long-term exposure to benzo [a] pyrene (B [a]P), a carcinogen in cigarette smoke. The blockage of AHR function considerably impaired suppressor of cytokine signaling 3 (SOCS3) negative feedback regulation and upregulated B [a]P-induced pro-inflammation. Signal transducer and activator of transcription 3 (STAT3) was activated by B [a] P due to AHR dysfunction in human adult retinal pigment epithelial cells (ARPE-19). The STAT3-inducible element revealed higher activity in AHR knockout cells with B [a] P treatment, but not in wild type ARPE-19 cells. Moreover, AHR dysfunction led to STAT3 hypo-ubiquitination and changed the STAT3–SOCS3 interaction. Increased STAT3–SOCS3 complex during AHR dysfunction by B [a] P was suppressed by nifuroxazide in ARPE-19 cells. Furthermore, the in vivo results showed that STAT3 inhibition during AHR impairment by long-term B [a] P exposure preserved the retina thickness and reversed the visual function in male C57Bl/6 mice. Overall, long-term B [a] P exposure may attenuate AHR function, dysregulating the homeostasis of the SOCS3–STAT3 axis with intensive STAT3 activation. This finding is significant given that the disintegration of the AHR–SOCS3 axis is a sensitive factor involved in AMD-like lesion development in the retina, revealing that the low AHR level may be associated with cigarette smoking or xenobiotics exposure, causing retina inflammation and damage.

AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated receptor that regulates the metabolism of several xenobiotics and participates in ocular inflammation. Although severe inflammation is a major risk of retinal damage, the underlying mechanism is not well established. In this study, to elucidate how AHR mediates inflammation homeostasis, we hypothesized that AHR expression may diminish during long-term exposure to benzo [a] pyrene (B [a]P), a carcinogen in cigarette smoke. The blockage of AHR function considerably impaired suppressor of cytokine signaling 3 (SOCS3) negative feedback regulation and upregulated B [a]P-induced pro-inflammation. Signal transducer and activator of transcription 3 (STAT3) was activated by B [a] P due to AHR dysfunction in human adult retinal pigment epithelial cells (ARPE-19). The STAT3-inducible element revealed higher activity in AHR knockout cells with B [a] P treatment, but not in wild type ARPE-19 cells. Moreover, AHR dysfunction led to STAT3 hypo-ubiquitination and changed the STAT3–SOCS3 interaction. Increased STAT3–SOCS3 complex during AHR dysfunction by B [a] P was suppressed by nifuroxazide in ARPE-19 cells. Furthermore, the in vivo results showed that STAT3 inhibition during AHR impairment by long-term B [a] P exposure preserved the retina thickness and reversed the visual function in male C57Bl/6 mice. Overall, long-term B [a] P exposure may attenuate AHR function, dysregulating the homeostasis of the SOCS3–STAT3 axis with intensive STAT3 activation. This finding is significant given that the disintegration of the AHR–SOCS3 axis is a sensitive factor involved in AMD-like lesion development in the retina, revealing that the low AHR level may be associated with cigarette smoking or xenobiotics exposure, causing retina inflammation and damage.

KW - Aryl hydrocarbon receptor

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KW - Retinal degeneration

KW - SOCS3

KW - STAT3

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