Enhanced cholinergic-mediated increase in the pro-inflammatory cytokine IL-6 in irritable bowel syndrome: role of muscarinic receptors.
OBJECTIVE
Irritable bowel syndrome (IBS) is a functional disorder, which has recently been linked to immune activation. We tested the hypothesis that the pro-inflammatory cytokine profile in IBS is driven by the cholinergic system and determined if the responses are mediated by muscarinic receptors.


METHODS
Eighty-eight subjects took part in two studies, 37 IBS patients (Rome II), 14 depressed patients, and 37 healthy volunteers. Eighteen IBS patients had diarrhea predominant IBS, 14 were alternators, and 5 were predominantly constipated. In study 1, blood was drawn for baseline measurement of growth hormone (GH) and cytokines IL-6, IL-8, and IL-10. Pyridostigmine 120 mg was administered orally and further blood sampling took place for 180 min. In study 2, patients with IBS, depressed patients, and healthy subjects underwent the pyridostigmine test on two separate occasions with procyclidine (antimuscarinic) pre-treatment on one test occasion. Both GH and IL-6 were monitored.


RESULTS
In study 1, baseline IL-6 (P= 0.003) and IL-8 levels (P= 0.001) were higher in IBS than in controls. Pyridostigmine stimulated the release of IL-6 and GH, but not IL-8 or IL-10; these responses were significantly augmented in IBS patients relative to controls. The IL-6 level following pyridostigmine administration correlated significantly with the symptom score (P < 0.01). In study 2, IL-6 rose following pyridostigmine in IBS but not depression and procyclidine blocked the rise. The GH response was abolished by procyclidine in all three groups.


CONCLUSIONS
IBS and major depression are characterized by a pro-inflammatory profile, whereas IBS patients alone exhibit an exaggerated muscarinic receptor-mediated IL-6 response.
Dinan
Timothy G
TG
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Clarke
Gerard
G
Quigley
Eamonn M M
EM
Scott
Lucinda V
LV
Shanahan
Fergus
F
Cryan
John
J
Cooney
John
J
Keeling
P W N
PW
D015746:Abdominal Pain / Q000097:blood / Q000175:diagnosis / Q000209:etiology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood; D043183:Irritable Bowel Syndrome / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000627:therapeutic use; D010147:Pain Measurement; D011352:Procyclidine / Q000627:therapeutic use; D011379:Prognosis; D011729:Pyridostigmine Bromide / Q000008:administration & dosage; D011863:Radioimmunoassay; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*
D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D016753:Interleukin-10; D011352:Procyclidine; D011729:Pyridostigmine Bromide