Glial‐derived neurotrophic factor regulates intestinal epithelial barrier function and inflammation and is therapeutic for murine colitis

Abstract

Although enteric glial cells (EGCs) have been demonstrated to play a key role in maintaining intestinal epithelial barrier integrity, it is not known how EGCs regulate this integrity. We therefore hypothesized that glial-derived neurotrophic factor (GDNF) produced by EGCs might be involved in this regulation. Here we investigated the role of GDNF in regulating epithelial barrier function in vivo. Recombinant adenoviral vectors encoding GDNF (Ad-GDNF) were administered intracolonically in experimental colitis induced by dextran sulphate sodium (DSS). The disease activity index (DAI) and histological score were measured. Epithelial permeability was assayed using Evans blue dye. The anti-apoptotic potency of GDNF in vivo was evaluated. The expression of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and myeloperoxidase (MPO) activity were measured by ELISA assay and/or RT-PCR. The expression of ZO-1, Akt, caspase-3, and NF-kappaB p65 was analysed by western blot assay. Our results showed that GDNF resulted in a significant reduction in enhanced permeability, inhibited MPO activity, IL-1beta and TNF-alpha expression, and increased ZO-1 and Akt expression. Moreover, GDNF strongly prevented apoptosis in vivo and significantly ameliorated experimental colitis. Our findings indicate that GDNF participates directly in restoring epithelial barrier function in vivo via reduction of increased epithelial permeability and inhibition of mucosal inflammatory response, and is efficacious in DSS-induced colitis. These findings support the notion that EGCs are able to regulate intestinal epithelial barrier integrity indirectly via their release of GDNF in vivo. GDNF is namely an important mediator of the cross-talk between EGCs and mucosal epithelial cells. GDNF may be a useful therapeutic approach to the treatment of inflammatory bowel disease.

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

“…In recent years it was consistently reported, that reduced levels of GDNF lead to morphological and functional abnormalities of IEB in mice comparable to the changes known in IBD (8,61,68). Conversely, it was shown that GNDF immunoreactivity was upregulated in experimental colitis and in specimen of patients with IBD, which was an effect predominately observed in enterocytes (52).…”

“…Zhang and coworkers (68) showed that application of recombinant adenoviral vectors encoding GDNF in a model of experimental colitis significantly reduced inflammation and loss of intestinal barrier functions. On the one hand, the underlying mechanism was attributed to anti-inflammatory effects, since GDNF blocked the secretion of various proinflammatory cytokines, such as TNF-␣ and interleukin-1␤.…”

Multifunctional Activity of a Small Tellurium Redox Immunomodulator Compound, AS101, on Dextran Sodium Sulfate-induced Murine Colitis

“…Colonic Epithelial Barrier Function Is Preserved by AS101 Treatment-The neurotrophin, GDNF, was shown to have a central role in protecting mucosal barrier function in experimental IBD and in IBD patients via up-regulation of PI3K/AKT pathway (29,52). Previously, we showed that AS101 induces GDNF production both in vitro and in vivo (38,39).…”

“…GDNF was found to be upregulated both in experimental IBD and in IBD patients. GDNF has strong anti-apoptotic activities in colonic epithelial cells, which depends on activation of MAPK and PI3K/AKT pathways (29,52). One form of epithelial cell injury in inflamed colonic mucosa in ulcerative colitis is reported to involve apoptosis of these cells (67).…”

NGF and nitrosative stress in patients with Huntington's disease

“…The putative link between changes in the MPO/WBC ratio, changes in nitrotyrosine levels and reduced production of neurotrophic factors is indirectly strengthened by reports that the administration of certain neurotrophic factors prompts an improvement in several neurodegenerative disorders: Zhang et al (2010), using an experimental colitis model, found that administration of GDNF inhibited MPO activity and improved symptoms [31].…”