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The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in modulating immune reactions in inflammatory bowel disease. Our aim was to assess the role of the HPA axis in the pathogenesis of immunomediated colitis in mice. Methods: Trinitrobenzene sulfonic acid (TNBS) colitis was induced in Balb/c mice. Sham operation (sham+TNBS) or bilateral adrenalectomy (Adex+TNBS) was performed 3 days later. Control groups underwent adrenalectomy without colitis induction (Adex) or were untreated [naïve mice (Naïve)]. Mice were monitored for survival, weight loss, and macroscopic and microscopic scores of colitis. FACS analysis of CD4+, CD8+, natural killer T lymphocytes, and serum levels of adrenocorticotropic hormone (ACTH), corticosterone (CS), interferon-γ (IFN-γ), interleukin-10 (IL-10), and IL-1β were measured. Production of prostaglandin E2 (PGE2) and binding capacity to glucocorticoid receptor (GR) in colonic mucosa were also assessed. Results: By day 7 following induction of colitis there was a marked increase in ACTH and CS levels in the colitis as compared with the control group (86 ± 6.5 pg/mL and 16 ± 1.9 pg/mL, and 23.3 ± 2 pg/mL and 2.8 ± 0.8 pg/mL, respectively). There was a decrease in ACTH and CS levels by day 28 in the colitis group, but the levels were still significantly higher than the levels in controls. Adrenalectomy markedly exacerbated colitis. The macroscopic and microscopic scores increased from 2.79 ± 0.03 and 2.0 ± 0.1 in the sham+TNBS group to 3.3 ± 0.3 and 3.2 ± 0.3 in the Adex+TNBS group. Survival and weight loss correlated with these differences. A significant increase in IL-10, IFN-γ, and PGE2 was noted in the Adex+TNBS group compared with the sham+TNBS group. Splenic CD4+ lymphocytes decreased in the sham+TNBS and Adex+TNBS groups as compared with control groups (Adex and naïve). The CD8+/CD4+ ratio was significantly higher in the Adex+TNBS compared with the sham+TNBS group. Colitis also caused a significant decrease in the specific binding capacity of labeled dexamethasone to colonic mucosa. Conclusions: TNBS induced colitis activated the HPA axis and reduced the sensitivity of the inflamed mucosa to circulating glucocorticoids. Adrenalectomy markedly exacerbated TNBS-induced colitis. The effect was associated with changes in the peripheral CD8+/CD4+ ratio and with a TH1 cytokine shift. Our results suggest that adrenocortical hormones play an important role in the regulation of the immune system in experimental colitis.