Crosstalk between interleukin-6 and corticotropin-releasing factor modulate submucosal plexus activity and colonic secretion.
BACKGROUND
Irritable bowel syndrome (IBS) is a common disorder of the gut with symptoms such as diarrhoea, constipation, abdominal pain and bloating, that are frequently exacerbated by stress. Circulating levels of the pro-inflammatory cytokine, interleukin-6 (IL-6), which can activate colonic enteric neurons, are elevated in IBS patients. These studies aim to explore the relationship between IL-6 and the stress peptide, corticotropin-releasing factor (CRF) in colonic submucosal neurons.


METHODS
Calcium imaging, Ussing chamber electrophysiology and immunohistochemistry were conducted on rat distal colons to investigate potential crosstalk between IL-6 and CRF.


RESULTS
Colonic secretions from the maternal separation rat model of IBS stimulated increases in intracellular calcium in naïve submucosal neurons via CRF1 receptors (n=15, p<0.05). Moreover, IL-6 (n=50, p<0.01) but not IL-1β (n=46, p>0.05) or TNFα (n=46, p>0.05) potentiated the CRF-evoked calcium response. CRF (1μM, 1h, n=5) stimulation also induced colonic secretion of IL-6 and inhibited the pro-secretory effects of IL-6 on colonic ion transfer (n=12).


CONCLUSIONS
These studies demonstrate the modulatory effects of CRF on colonic IL-6 secretion, neuronal activation and secretory function. These findings may provide an insight into the molecular mechanisms underlying symptom flares in IBS during periods of high stress.
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Physiology, University College Cork, Cork, Ireland. d.omalley@ucc.ie
Dervla
D
O'Malley
John F
JF
Cryan
Timothy G
TG
Dinan
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D043183:Irritable Bowel Syndrome / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008426:Maternal Deprivation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013368:Submucous Plexus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology
D015850:Interleukin-6; D018019:Receptors, Corticotropin-Releasing Hormone; D019947:Receptors, Interleukin-6; D003346:Corticotropin-Releasing Hormone; D002118:Calcium