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NEUROREGULATION AND MOTILITY

Toxin B of Clostridium difficile activates human VIP submucosal neurons, in part via an IL-1-dependent pathway

¹Institut National de la Santé et de la Recherche Médicale U539 and ²Department of Gastroenterology, Hôtel-Dieu Hospital, 44035 Nantes, France; ³Technische Universität München, Department of Human Biology, 85350 Freising; ⁴Department of Toxicology, Hannover Medical School, D-30623 Hannover, Germany

Submitted 8 November 2002 ; accepted in final form 30 May 2003

This study investigated whether toxin B of Clostridium difficile can activate human submucosal neurons and the involved pathways. Isolated segments of human colon were placed in organ culture for 3 h in the presence of toxin B or IL-1. Whole mounts of internal submucosal plexus were stained with antibodies against c-Fos, neuron-specific enolase (NSE), vasoactive intestinal polypeptide (VIP), and substance P (SP). The membrane potential (V_m) response of submucosal neurons to local application of toxin B and IL-1 was determined by a multisite optical recording technique. Toxin B (0.1 to 10 ng/ml) increased the proportion of c-Fos-positive neurons dose dependently compared with the control. In the presence of toxin B (10 ng/ml), most c-Fos-positive neurons were immunoreactive for VIP (79.8 ± 22.5%) but only 19.4 ± 14.0% for SP. Toxin B induced a rapid rise in IL-1 mRNA level and a sixfold increase in IL-1 protein in supernatant after 3 h of incubation. c-Fos expression induced by toxin B was reduced dose dependently by IL-1 receptor antagonist (0.1-10 ng/ml). IL-1 significantly increased c-Fos expression in submucosal neurons compared with the control (34.2 ± 10.1 vs. 5.1 ± 1.3% of NSE neurons). Microejection of toxin B had no effect on the V_m of enteric neurons. Evidence of a direct excitatory effect of IL-1 on V_m was detected in a minority of enteric neurons. Therefore, toxin B of C. difficile activates VIP-positive submucosal neurons, at least in part, via an indirect IL-1-dependent pathway.

c-Fos; voltage-sensitive dyes; cytokines; human submucosal plexus

This article has been cited by other articles:

				G. K. A. Meyer, A. Neetz, G. Brandes, D. Tsikas, J. H. Butterfield, I. Just, and R. Gerhard Clostridium difficile Toxins A and B Directly Stimulate Human Mast Cells Infect. Immun., August 1, 2007; 75(8): 3868 - 3876. [Abstract] [Full Text] [PDF]

				D. E. Voth and J. D. Ballard Clostridium difficile Toxins: Mechanism of Action and Role in Disease Clin. Microbiol. Rev., April 1, 2005; 18(2): 247 - 263. [Abstract] [Full Text] [PDF]