Modulation of enteric neurons by interleukin‐6 and corticotropin‐releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome

• Published in: The Journal of physiology Vol. 592; no. 23; pp. 5235 - 5250
• Main Authors: Buckley, Maria M., O'Halloran, Ken D., Rae, Mark G., Dinan, Timothy G., O'Malley, Dervla
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.12.2014; BlackWell Publishing Ltd
• Subjects: Adolescent; Adult; Aged; Alimentary; Animals; Antibodies, Monoclonal - administration & dosage; Case-Control Studies; Disease Models, Animal; Enteric Nervous System - physiopathology; Female; Gastrointestinal Motility - physiology; Humans; Interleukin-6 - physiology; Irritable Bowel Syndrome - etiology; Irritable Bowel Syndrome - physiopathology; Irritable Bowel Syndrome - therapy; Male; Middle Aged; Myenteric Plexus - physiopathology; Neuroimmunomodulation - physiology; Neurosecretory Systems - physiopathology; Pain Threshold - drug effects; Pain Threshold - physiology; Pyrimidines - administration & dosage; Pyrroles - administration & dosage; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Receptors, Corticotropin-Releasing Hormone - physiology; Receptors, Interleukin-6 - antagonists & inhibitors; Receptors, Interleukin-6 - physiology; Visceral Pain - etiology; Visceral Pain - physiopathology; Visceral Pain - therapy; Young Adult
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2014.279968

Key points Hyperactivity of the stress system and low‐grade immune activation characterize the functional bowel disorder irritable bowel syndrome (IBS). These studies show that interleukin (IL)‐6 and IL‐8 and the stress hormone corticotropin‐releasing factor (CRF), present in IBS plasma, have functional effects on gastrointestinal activity by stimulating myenteric neurons and colonic contractions. Moreover, in the Wistar Kyoto rat model of IBS, which exhibits altered gastrointestinal motility and visceral pain sensitivity, blocking IL‐6 and/or CRF1 receptors alleviates these IBS‐like symptoms. Underlying these effects are altered colonic protein expression of tight junction proteins which regulate gut barrier function and the T‐type calcium channel CaV3.2, which has been linked to visceral pain. These findings demonstrate the importance of the enteric nervous system and intestinal physiology in bowel dysfunction. The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin‐6 (IL‐6) and corticotropin‐releasing factor receptor (CRFR) 1 in visceral pain and stress‐induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti‐IL‐6 receptor antibodies (xIL‐6R, 0.5 mg kg−1 i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg−1 i.p). Post‐intervention, the pain threshold to colorectal distension and stress‐induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro‐stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL‐6, IL‐8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL‐6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress‐induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain‐associated T‐type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL‐6 and CRF1 receptors is effective in alleviating IBS‐like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.