Gastroenterology

Gastroenterology

Volume 124, Issue 7, June 2003, Pages 1748-1757
Gastroenterology

Clinical-alimentary tract
Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells

https://doi.org/10.1016/S0016-5085(03)00404-9Get rights and content

Abstract

Background & Aims:

Ablation of the enteric glia leads to a fulminant hemorrhagic jejunoileitis. We hypothesized that glial-derived neurotrophic factor (GDNF) may be involved in mucosal protection of the gut. Therefore, we examined the regulation of GDNF and its receptor (GFR-α1) in colonic inflammation and its effects on colonic epithelial cell apoptosis.

Methods:

The expression of GDNF and GFR-α1 was investigated in experimental colitis of rats and in human inflammatory bowel disease (IBD). GDNF-induced activation of Akt (protein kinase B [PKB]) and mitogen-activated protein kinase (MAPK) in the colonic epithelial cell lines HT-29 and SW480 was studied. Furthermore, the antiapoptotic potency of GDNF in SW480 cells was evaluated.

Results:

GDNF was specifically up-regulated in experimental rat colitis and in IBD. In contrast, GFR-α1 was constitutively expressed in rat and human colonic epithelium. GDNF potently activated MAPK and Akt (PKB) in colonic epithelial cells. Moreover, GDNF strongly prevented apoptosis in SW480 cells. Our data show that GDNF-mediated protection against apoptosis depends on activation of the MAPK and phosphatidylinositol 3-kinase/Akt (PKB) pathways.

Conclusions:

GDNF is up-regulated in IBD and has strong antiapoptotic properties in colonic epithelial cells. This points to a novel role of the neurotrophic factor GDNF for mucosal protection and regeneration in IBD.

Section snippets

Antibodies and reagents

Antibodies used in this study were as follows: p42/44 mitogen-activated protein kinase (MAPK) and Akt (protein kinase B [PKB]) (Cell Signaling Technology, Beverly, MA), GDNF receptor (GFR)-α1 antibody (Transduction Labs/Becton Dickinson, Heidelberg, Germany), GDNF antibodies (R & D Systems, Wiesbaden, Germany; Santa Cruz Biotechnology, Heidelberg, Germany), cleaved poly(ADP-ribose)polymerase (PARP) antibody (Biosource, Camarillo, CA), β -actin antibody (Dr. Andre Menke, University of Ulm), and

GDNF and GFR-α1 in normal and inflamed rat colonic epithelium

In colonic tissue sections of control rats, a minor GDNF immunoreactivity could be detected at the surface epithelium of the colonic mucosa (Figure 1A) One and 3 days after induction of colitis, we observed a stronger GDNF staining at the colonic epithelium reaching more toward the crypt base compared with controls (Figure 1B and C). At day 21, the epithelial GDNF staining had decreased to the basal level (Figure 1D). As shown in Figure 1E, the myenteric plexus of rats was also GDNF positive.

Discussion

In this report, we show that GDNF is up-regulated in IBD and experimental colitis and that this neurotrophic factor has strong antiapoptotic effects on colonic epithelial cells. Our data strongly suggest a novel endogenous regulatory function of GDNF in the protection of the epithelial lining during mucosal inflammation.

The expression of GDNF in the gut is crucial for the neuronal development of the gut. Mice lacking GDNF or its receptor, GFR-α, among other defects, fail to develop an intact

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