Neurotrophin expression in the adrenal gland in experimental colitis suggest a neuroendocrine regulatory pathway

Abstract

Introduction: We have shown that neurotrophins like nerve growth factor (NGF) and neurotrophin-3 (NT-3) are important neuroimmune regulators of inflammation in experimental colitis and are upregulated in the inflamed gut of patients with inflammatory bowel disease. In this study we wanted to investigate if neurotrophins can act as neuroendocrine mediators during inflammation through expression in the adrenal glands during the timecourse of experimental colitis in rats. Methods: Colitis was induced in adult Sprague Dawley rats (n=3 each group) by a TNB/Ethanol enema (50mg/kg TNB in 50% EtOH). The animals were sacrificed at 8h, 12h, ld, 3d, 5d, 7d, 14d, 21d and 28 days after induction of colitis and a macroscopic damage score of the distal colon was taken. The adrenal glands were dissected and processed for immunohistochemistry (ABC) and western blotting. ABC-staining and western analysis was performed for NGF, BDNF (brain-derived neurotropic factor), NT-3, GDNF (glial-cell-line-derived neurotrophic factor), CD3 (used as T-cell marker) and PGP 9.5 (pan-neuronal marker). Results: There was a marked upregulation of NGF expression in circumscript areas of the adrenal cortex until 24 h with a decline to control levels after 7 days of colitis. BDNF and NT-3 were markedly upregulated in different areas of the adrenal cortex until ld with with a slow decline to basal levels after 14 days. GDNF again was sharply upregulated in the the adrenal medulla from 8h to ld and there was a significant expression until 14 days after induction of colitis. CD3 (TCR) expression was present in the cortex as well as in the medulla and sharply upregulated in the same areas as the neurotrophins until ld with a slow decline until 28 days. PGP 9,5 was only expressed in the adrenal medulla. Western blot analysis confirmed the quantitative changes of neurotrophin expression in the adrenal gland during the different timepoints. Discussion: The marked expression of neurotrophins in different sections of the adrenal cortex and medulla indicate that these neurotrophins regulate the endocrine reaction to the inflammatory process in the colon. Since neurotrophins are also potent neuro-immuno mediators we speculate that a neuro-immuno-endocrine interaction exists during chronic inflammation in the colon. Disturbance of this system might contribute tO the pathophysiology of human inflammatory bowel disease.