摘要
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 beta. @@@ 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 beta 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 bblocker, markedly ameliorated the inflammatory response and IL1 beta 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 IL1b than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a beta 2-agonist, induced a greater IL1 beta expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1 beta 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 beta activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-kappa B to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that beta blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.
- 出版日期2018
- 单位中南大学