Prolonged IL-1β exposure alters neurotransmitter and electrically induced Ca²⁺responses in the myenteric plexus

Abstract

BACKGROUND Infection and inflammatory diseases of the gut results in profound changes of intestinal motor function. Acute administration of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) was shown to have excitatory and neuromodulatory roles in the myenteric plexus. Here we aimed to study the effect of prolonged IL-1beta incubation on the response of myenteric neurones to different stimuli. METHODS Longitudinal muscle myenteric plexus preparations (LMMP's) of the guinea pig jejunum were incubated for 24 h in medium with or without IL-1beta. After loading with Fluo-4, calcium imaging was used to visualize activation of neurones. The response to application of serotonin (5-HT), substance P (SP) and ATP or to electrical fibre tract stimulation (eFTS) was tested. Expression of nNOS, HuD, calbindin and calretinin was compared by immunohistochemistry. KEY RESULTS IL-1beta concentration-dependently influenced the neuronal responsiveness and duration of the [Ca(2+)](i) rises to 5-HT and ATP, while it also affected the Ca(2+)-transient amplitudes induced by 5-HT, ATP and SP. Ca(2+)-transients in response to eFTS were observed in significantly more neurones per ganglion after IL-1beta (10(-10) and 10(-11) mol L(-1)). Peak [Ca(2+)](i) rise after eFTS was concentration-dependently decreased by IL-1beta. The duration of the [Ca(2+)](i) rise after eFTS was prolonged after IL-1beta 10(-12) mol L(-1). IL-1beta (10(-9) mol L(-1)) incubation did not affect the number of nNOS, calretinin and calbindin expressing neurones, nor did it induce neuronal loss (HuD). CONCLUSIONS & INFERENCES In this study, IL-1beta differentially modulates the neuronal response to eFTS and neurotransmitter application in the myenteric plexus of guinea pigs. This cytokine could be implicated in the motility disturbances observed during gastrointestinal inflammation.

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

“…Cytokine-induced modulation of enteric neurons can subsequently alter GI motility, absorption, secretion, and blood flow. Moreover, mucosal ion transport and epithelial permeability, in addition to enhancement of cholinergically mediated neurotransmission, are altered by proinflammatory cytokines such as IL-6 and IL-1␤ (24,30). Further support for IL-6 as a secretory cytokine is provided in its ability to suppress the inhibitory and antisecretory effects of norepinephrine by blocking its release from sympathetic fibers (37).…”

Immunoinflammation and functional gastrointestinal disorders

“…Inflammatory mediators released by the infiltration may induce the alteration of GI motility. [18] An elevation of inflammatory factors, including IL-1β, TNF-α, and IL-6, was found in both IBD and postoperative ileus patients and it should be noted that in IBS patients, no pathomorphologic changes were observed, whereas the elevation of IL-6 was found in the region with gastrointestinal dyskinesis. [19] A study on gastroesophageal reflux disease showed that when the esophageal epithelial cells come in contact with the gastric juice, a great deal of IL-1β and IL-6 could be produced to reduce esophageal muscle contractility.…”

“…[18] As the concentration of IL-1β in smooth muscle ( in vitro ) perfusion groove was elevated from 10 -9 mol/L to 10 -8 mol/L, the open rate of Ca 2+ was increased from 17.3% to 24.7%; the result has indicated that IL-1β may directly act on Ca 2+ channel on GI smooth muscle cell membrane, thus affecting on the intestinal motility function.…”

Pro- and Antiphlogistic Concentration of Cytokines in Rats’ Serum after Long-Term Administration of Omeprazole and the Simultaneous Injection of Multiprobiotics and Omeprazole

“…Меха-нізм такого впливу багатогранний. Прозапальні цитокіни безпосередньо впливають на парієтальні клітини і пригнічують секрецію HCl, стимулюють синтез і виділення гастрину [27], пригнічують мото-рику травного тракту [17,23]. Що стосується секре-ції гастрину, на наш погляд, важливою є робота, в якій показано, що ІЛ-1β і ФНП-α можуть прямо ре-гулювати експресію гену гастрину через мітоген-активовану протеїнкіназу-і протеїнкіназа С-залеж-ний механізм [27].…”

“…Kindt та співат. [23] показали, що однора-зове введення IЛ-1β відіграє збуджуючу і нейромо-дулюючу роль в міентеральному плетиві, проте тривала інкубація IЛ-1β з препаратом міентераль-ного плетива гладеньких м'язів порожньої кишки мурчаків дозо-залежно впливає на нейрональну відповідь і зростання концентрації іонізованого На сьогодні доведено, що IЛ-1β є сильним інгі-бітором скорочень гладеньких м'язових волокон тонкої кишки, клубової і товстої кишок у відповідь на ацетилхолін [4]. В цій роботі показано, що попе-реднє введення блокатора синтезу білка циклогек-симіду блокувало викликане IЛ-1β гальмування скорочень тонкої кишки, стимульованих ацетилхо-ліном, що дало авторам підстави припустити залу-чення нового синтезованого білку в цей ефект.…”