Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life

Xiaoying S. Zhong, John Winston, Xiuju Luo, Kevin T. Kline, Syed Z. Nayeem, Yingzi Cong, Tor C. Savidge, Roderick H. Dashwood, Don W. Powell, Qingjie Li

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background & Aims: Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β. Methods: We developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid. Results: Aggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1β and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a β-blocker, markedly ameliorated the inflammatory response and IL1β overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1β than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a β2-agonist, induced a greater IL1β expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1β activation in human THP-1–derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol. Conclusions: NI sensitizes the colon epithelium for exacerbated IL1β activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that β blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.

Original languageEnglish (US)
Pages (from-to)65-78
Number of pages14
JournalCMGH
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Inflammation
Wounds and Injuries
Lipopolysaccharides
Inflammatory Bowel Diseases
Disease Susceptibility
Avian Reticuloendotheliosis
Epigenomics
Propranolol
Histones
Epinephrine
Epithelium
Macrophages
Trinitrobenzenes
Yohimbine
Sulfonic Acids
Gastrointestinal Diseases
Adrenalectomy
Interleukin-1
Oncogenes
Norepinephrine

Keywords

  • Early Life Adversity
  • Epinephrine
  • Histone Acetylation
  • Inflammatory Bowel Disease
  • NF-κB

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life. / Zhong, Xiaoying S.; Winston, John; Luo, Xiuju; Kline, Kevin T.; Nayeem, Syed Z.; Cong, Yingzi; Savidge, Tor C.; Dashwood, Roderick H.; Powell, Don W.; Li, Qingjie.

In: CMGH, Vol. 6, No. 1, 01.01.2018, p. 65-78.

Research output: Contribution to journalArticle

Zhong, Xiaoying S. ; Winston, John ; Luo, Xiuju ; Kline, Kevin T. ; Nayeem, Syed Z. ; Cong, Yingzi ; Savidge, Tor C. ; Dashwood, Roderick H. ; Powell, Don W. ; Li, Qingjie. / Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life. In: CMGH. 2018 ; Vol. 6, No. 1. pp. 65-78.
@article{5ddac433154b46bfb47aa5220c832bf5,
title = "Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life",
abstract = "Background & Aims: Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β. Methods: We developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid. Results: Aggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1β and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a β-blocker, markedly ameliorated the inflammatory response and IL1β overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1β than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a β2-agonist, induced a greater IL1β expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1β activation in human THP-1–derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol. Conclusions: NI sensitizes the colon epithelium for exacerbated IL1β activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that β blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.",
keywords = "Early Life Adversity, Epinephrine, Histone Acetylation, Inflammatory Bowel Disease, NF-κB",
author = "Zhong, {Xiaoying S.} and John Winston and Xiuju Luo and Kline, {Kevin T.} and Nayeem, {Syed Z.} and Yingzi Cong and Savidge, {Tor C.} and Dashwood, {Roderick H.} and Powell, {Don W.} and Qingjie Li",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jcmgh.2018.02.014",
language = "English (US)",
volume = "6",
pages = "65--78",
journal = "Cellular and Molecular Gastroenterology and Hepatology",
issn = "2352-345X",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life

AU - Zhong, Xiaoying S.

AU - Winston, John

AU - Luo, Xiuju

AU - Kline, Kevin T.

AU - Nayeem, Syed Z.

AU - Cong, Yingzi

AU - Savidge, Tor C.

AU - Dashwood, Roderick H.

AU - Powell, Don W.

AU - Li, Qingjie

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background & Aims: Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β. Methods: We developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid. Results: Aggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1β and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a β-blocker, markedly ameliorated the inflammatory response and IL1β overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1β than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a β2-agonist, induced a greater IL1β expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1β activation in human THP-1–derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol. Conclusions: NI sensitizes the colon epithelium for exacerbated IL1β activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that β blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.

AB - Background & Aims: Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β. Methods: We developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid. Results: Aggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1β and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a β-blocker, markedly ameliorated the inflammatory response and IL1β overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1β than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a β2-agonist, induced a greater IL1β expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1β activation in human THP-1–derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol. Conclusions: NI sensitizes the colon epithelium for exacerbated IL1β activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that β blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.

KW - Early Life Adversity

KW - Epinephrine

KW - Histone Acetylation

KW - Inflammatory Bowel Disease

KW - NF-κB

UR - http://www.scopus.com/inward/record.url?scp=85048497430&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048497430&partnerID=8YFLogxK

U2 - 10.1016/j.jcmgh.2018.02.014

DO - 10.1016/j.jcmgh.2018.02.014

M3 - Article

AN - SCOPUS:85048497430

VL - 6

SP - 65

EP - 78

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

SN - 2352-345X

IS - 1

ER -