title: In vivo neutralization of IL-6 receptors ameliorates gastrointestinal dysfunction in dystrophin-deficient mdx mice.
abstract: Duchenne muscular dystrophy (DMD) is a fatal disease characterized by progressive deterioration and degeneration of striated muscle. A mutation resulting in the loss of dystrophin, a structural protein which protects cells from contraction-induced damage, underlies DMD pathophysiology. Damage to muscle fibers results in chronic inflammation and elevated levels of proinflammatory cytokines such as interleukin-6 (IL-6). However, loss of cellular dystrophin also affects neurons and smooth muscle in the gastrointestinal (GI) tract with complaints such as hypomotility, pseudo-obstruction, and constipation reported in DMD patients.
  
  
  
  Using dystrophin-deficient mdx mice, studies were carried out to examine colonic morphology and function compared with wild-type mice. Treatment with neutralizing IL-6 receptor antibodies (xIL-6R) and/or the corticotropin-releasing factor (CRF) 2 receptor agonist, urocortin 2 (uro2) was tested to determine if they ameliorated GI dysfunction in mdx mice.
  
  
  
  Mdx mice exhibited thickening of colonic smooth muscle layers and delayed stress-induced defecation. In organ bath studies, neurally mediated IL-6-evoked contractions were larger in mdx colons. In vivo treatment of mdx mice with xIL-6R normalized defecation rates and colon lengths. Uro2 treatment did not affect motility or morphology. The potentiated colonic contractile response to IL-6 was attenuated by treatment with xIL-6R.
  
  
  
  These findings confirm the importance of dystrophin in normal GI function and implicate IL-6 as an important regulator of GI motility in the mdx mouse. Inhibition of IL-6 signaling may offer a potential new therapeutic strategy for treating DMD-associated GI symptoms.
authors.affiliation: Department of Physiology, University College Cork, Cork, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Manning
authors.affiliation: Department of Physiology, University College Cork, Cork, Ireland.|APC Microbiome Institute, University College Cork, Cork, Ireland.
authors.forename: M M
authors.initials: MM
authors.lastname: Buckley
authors.affiliation: Department of Physiology, University College Cork, Cork, Ireland.
authors.forename: K D
authors.initials: KD
authors.lastname: O'Halloran
authors.affiliation: Department of Physiology, University College Cork, Cork, Ireland.|APC Microbiome Institute, University College Cork, Cork, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: O'Malley
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency*; D005767:Gastrointestinal Diseases / Q000378:metabolism* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009924:Organ Culture Techniques; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D016189:Dystrophin; D015850:Interleukin-6; D019947:Receptors, Interleukin-6
keywords: colonic contractions; colonic transit; interleukin-6 receptor; urocortin 2