Targeting IL-4/IL-13 signaling to alleviate oral allergen–induced diarrhea

Background

Intestinal anaphylaxis (manifested by acute diarrhea) is dependent on IgE and mast cells.

Objective

We aimed to define the respective roles of IL-4 and IL-13 and their receptors in disease pathogenesis.

Methods

Wild-type mice and mice deficient in IL-4, IL-13, and IL-13 receptor (IL-13R) α1 (part of the type 2 IL-4 receptor [IL-4R]) were sensitized with ovalbumin (OVA)/aluminum potassium sulfate and subsequently given repeated intragastric OVA exposures. The IL-4Rα chain was targeted with anti-IL-4Rα mAb before or after intragastric OVA exposures.

Results

IL4^−/− (and IL4/IL13^−/−) mice produced almost no IgE and were highly resistant to OVA-induced diarrhea, whereas allergic diarrhea was only partially impaired in IL13^−/− and IL13Rα1^−/− mice. IL13Rα1-deficient mice had decreased IgE levels, despite having normal baseline IL-4 levels. Intestinal mast cell accumulation and activation also depended mainly on IL-4 and, to a lesser extent, on IL-13. Prophylactic anti-IL-4Rα mAb treatment, which blocks all IL-4 and IL-13 signaling, suppressed development of allergic diarrhea. However, treatment with anti–IL-4Rα mAb for 7 days only partially suppressed IgE and did not prevent intestinal diarrhea.

Conclusion

Endogenously produced IL-13 supplements the ability of IL-4 to induce allergic diarrhea by promoting oral allergen sensitization rather than the effector phase of intestinal anaphylaxis.

Key words: Allergy, anaphylaxis, IL-4, IL-13, IL-13Rα1, intestine, mast cell

Abbreviations used: alum, Aluminum potassium sulfate, IL-4R, IL-4 receptor, IL-13R, IL-13 receptor, MMCP1, Mouse mast cell protease 1, OVA, Ovalbumin, STAT6, Signal transducer and activator of transcription 6