In vivo neutralization of IL ‐6 receptors ameliorates gastrointestinal dysfunction in dystrophin‐deficient mdx mice

Background 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. Methods 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. Key Results 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. Conclusions & Inferences 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.