Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life.
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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)1. 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 IL1 and other cytokines. In parallel with exacerbated loss of inhibitor ofkappa 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 -blocker, markedly ameliorated the inflammatory response and IL1 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 IL1 than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a 2-agonist, induced a greater IL1 expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1 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 IL1 activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-B to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novelparadigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.
Zhong, X. S., Winston, J. H., Luo, X., Kline, K. T., Nayeem, S. Z., Cong, Y., ... Li, Q.
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Zhong, Xiaoying S||Winston, John H||Luo, Xiuju||Kline, Kevin T||Nayeem, Syed Z||Cong, Yingzi||Savidge, Tor C||Dashwood, Roderick H||Powell, Don W||Li, Qingjie
