TNFα causes thrombin-dependent vagal neuron apoptosis in inflammatory bowel disease.

Abstract

BACKGROUND:

The role of peripheral tumor necrosis factor alpha (TNFα) in inflammatory bowel disease (IBD) is well established, but its central nervous system (CNS) effects are not understood. Thrombin, another mediator of inflammation in IBD, has been implicated in CNS vagal neuron apoptosis in the dorsal motor nucleus of the vagus (DMV). This study evaluates DMV TNFα exposure, characterizes effects of TNFα on DMV neurons, and identifies a relationship between DMV TNFα and thrombin in IBD.

METHODS:

2,4,6-Trinitrobenzene sulfonic acid was administered via enema to induce colonic inflammation in rats. TNFα in serum, cerebrospinal fluid (CSF), and DMV tissues were determined by ELISA and DMV TNFα expression by quantitative reverse transcription PCR (RT-PCR). TNFα was administered into the fourth intracerebral ventricle (4 V) adjacent to the DMV, with and without blockade of TNF receptor 1 (TNFR1) and the thrombin receptor proteinase-activated receptor 1 (PAR1). Immunofluorescence was used to evaluate microglial activation (Cd11b) and prothrombin presence in DMV sections. Apoptosis was examined using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) and activated caspase-3 immunofluorescence.

RESULTS:

IBD is associated with increased TNFα protein in serum, CSF, and DMV tissue; DMV TNFα transcription is also increased. TNFα (4 V) caused a 54 % increase in microglial activation, a 27 % increase in DMV prothrombin protein, and a 31 % increase in vagal neuron apoptosis by TUNEL. There was a 52 % increase in activated caspase-3 immunofluorescence in TNFα-treated animals (p < 0.05). All effects of 4 V TNFα were prevented by TNFR1 blockade. TNFα-induced apoptosis was prevented by PAR1 blockade.

CONCLUSIONS:

IBD is associated with DMV exposure to TNFα, causing excess DMV prothrombin and vagal apoptosis.

• Authors: Danielle Fritze, Weizhen Zhang, Ji-Yao Li, Biaoxin Chai, Michael W Mulholland
• Journal: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract (J Gastrointest Surg) Vol. 18 Issue 9 Pg. 1632-41 (Sep 2014) ISSN: 1873-4626 [Electronic] United States
• PMID: 24961441 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CD11b Antigen
• RNA, Messenger
• Receptor, PAR-1
• Receptors, Tumor Necrosis Factor, Type I
• Tumor Necrosis Factor-alpha
• Trinitrobenzenesulfonic Acid
• Prothrombin
• Thrombin
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• CD11b Antigen (metabolism)
• Caspase 3 (metabolism)
• Inflammatory Bowel Diseases (chemically induced, metabolism)
• Male
• Microglia (drug effects, metabolism)
• Neurons, Efferent (drug effects, metabolism)
• Prothrombin (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, PAR-1 (antagonists & inhibitors)
• Receptors, Tumor Necrosis Factor, Type I (antagonists & inhibitors)
• Thrombin (metabolism)
• Trinitrobenzenesulfonic Acid
• Tumor Necrosis Factor-alpha (genetics, metabolism, pharmacology)
• Vagus Nerve