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Interleukin-4 modulates cholinergic neural control of mouse small intestinal longitudinal muscle
J Goldhill1, S C Morris, C Maliszewski
1Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20815, USA.
Abstract:
Interleukin-4 contributes to expulsion of certain gastrointestinal parasites and causes intestinal mucosal mastocytosis. Because mast cell-derived mediators are spasmogenic, potentially causing parasitic expulsion, we investigated the effect of interleukin-4 on smooth muscle and the mast cell and mediator dependency of this effect. BALB/c, mast cell-deficient W/Wv mice, 5-lipoxygenase-efficient mice, and their littermate controls were injected with interleukin-4-anti-interleukin-4 antibody complexes that chronically increase serum interleukin-4 levels. Mid-small intestinal segments, hung longitudinally in organ baths, were stimulated electrically or by agonists. The cholinergic response to electrical field stimulation was significantly increased by interleukin-4 treatment in BALB/c but not W/Wv mice. The enhanced cholinergic contraction was not due to increased acetylcholine responsiveness but was dependent on leukotriene D4, since it was reversed by leukotriene D4 receptor antagonism, and not observed in 5-lipoxygenase knock-out mice. Leukotriene D4 responsiveness was unaffected by interleukin-4 treatment. We conclude that interleukin-4 amplifies cholinergic excitation through a mast cell and leukotriene D4-dependent mechanism.
Insights
Interleukin-4 (IL-4) amplifies gut smooth muscle contractions via mast cells and leukotriene D4. This IL-4 effect is crucial for expelling gastrointestinal parasites.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- Interleukin-4 (IL-4) plays a role in parasite expulsion and mast cell activation in the gut.
- Mast cell mediators can induce spasms, potentially aiding parasite removal.
- The precise mechanism of IL-4's effect on intestinal smooth muscle and its dependence on mast cells and mediators requires elucidation.
Purpose of the Study:
- To investigate the impact of IL-4 on intestinal smooth muscle function.
- To determine the role of mast cells and specific mediators in IL-4-induced smooth muscle responses.
- To elucidate the pathway through which IL-4 influences cholinergic excitation in the gastrointestinal tract.
Main Methods:
- Utilized BALB/c, mast cell-deficient W/Wv mice, and 5-lipoxygenase-efficient mice.
- Administered IL-4-anti-IL-4 antibody complexes to elevate serum IL-4 levels.
- Assessed smooth muscle contractility in isolated intestinal segments using electrical field stimulation and agonist stimulation in organ baths.
Main Results:
- IL-4 treatment significantly enhanced cholinergic responses in wild-type mice but not in mast cell-deficient mice.
- The enhanced contraction was dependent on leukotriene D4 (LTD4), as confirmed by receptor antagonism and lack of effect in 5-lipoxygenase knockout mice.
- IL-4 did not alter the responsiveness to LTD4 itself, indicating amplification rather than sensitization.
Conclusions:
- Interleukin-4 amplifies cholinergic excitation of intestinal smooth muscle.
- This amplification is mediated by mast cells and leukotriene D4.
- The findings provide a mechanism for IL-4's role in gastrointestinal parasite expulsion.