Colonic soluble mediators from the maternal separation model of irritable bowel syndrome activate submucosal neurons via an interleukin-6-dependent mechanism

Abstract

Irritable bowel syndrome (IBS) is characterized by episodic bouts of abdominal pain, bloating, and altered bowel habit. Accumulating evidence has linked immune activation with IBS, including reports of increases in circulating levels of the proinflammatory cytokine interleukin (IL)-6. However, it is unknown whether IL-6 contributes directly to disease manifestation. As enteric nervous activity mediates motility and secretory function, the aims of this study were to determine the effects of IL-6 on submucosal neurons and related gastrointestinal (GI) function. In these studies, we examined the colons of maternally separated (MS) rats, which exhibit elevated circulating levels of IL-6 in addition to GI dysfunction. To our knowledge, these studies are the first to provide evidence of the sensitivity of submucosal neurons to colonic secretions from MS rats (n = 50, P < 0.05), thus recapitulating clinical biopsy data. Moreover, we demonstrated that the excitatory action is IL-6 dependent. Thereafter, the impact of IL-6 on neuronal and glial activation and absorpto/secretory function was pharmacologically characterized. Other proinflammatory cytokines including IL-8 (n = 30, P > 0.05), IL-1β (n = 56, P > 0.05), and TNF-α (n = 56, P > 0.05) excited fewer neurons. Both muscarinic and nicotinic cholinergic receptors participate in the effect and cause downstream activation of ERK, JAK-STAT, and NF-κB signaling cascades. Functionally, IL-6 increases transepithelial resistance and enhances neurally and cholinergically mediated ion transport. These data provide a role for IL-6 in colonic secretory functions and relate these effects to GI dysfunction in an animal model of IBS, thereby elucidating a potential relationship between circulating levels of IL-6 and aberrant GI function.

Assessment of sex specific endocrine disrupting effects in the prenatal and pre-pubertal rodent brain

“…Interestingly, no immune related endpoints have been investigated to date in sub-adult animals, even though some immune cells like microglia (Wood 2011, Wu, Tan et al 2013) and neutrophils (Molero, Garcia-Duran et al 2002, Shindo, Moore et al 2013) have been found to express estrogen receptors, impact sexually dimorphic development (O’Malley, Liston et al 2011) and the immune system is reciprocally influenced by the hypothalamus. Interactions between endocrine disrupting compounds and neuroimmune cells, such as microglia, may be mechanisms by which developmental sexually dimorphic diseases, such as autism occur and thus an important area of focus for future studies.…”

Modulation of lipopolysaccharide-induced neuronal response by activation of the enteric nervous system

“…This pleiotropic cytokine has a central role in generating acute-phase responses, inflammation and lymphocyte differentiation. Concerning the ENS, IL-6 increases neuronal excitability [57-59], and can participate in gastrointestinal dysfunction associated with intestinal inflammation or irritable bowel syndrome. In addition, IL-6 can also reduce enteric neuronal survival [60].…”

Stress and Chronic Pelvic Pain

“…61 Rodents exposed to NMS have also demonstrated increased growth factor and cytokine expression in the distal colon, including nerve growth factor (NGF), interleukin (IL)-6, IL-1β, IL-2, IL-4, IL-10, and interferon (IFN)-γ. [94][95][96][97] A follow-up study revealed that CRF and IL-6 interact to potentiate calcium responses in submucosal neurons and thereby alter colonic secretory activity. 98 Colons from NMS rats have also demonstrated increased paracellular permeability, myeloperoxidase activity, and mucosal mast cell infiltration.…”