IL-13Ralpha2 reverses the effects of IL-13 and IL-4 on bronchial reactivity and acetylcholine-induced Ca+ signaling.
BACKGROUND
The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13Ralpha2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13Ralpha2 remains vague.


METHODS
Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca(2+) signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy.


RESULTS
IL-4 or IL-13 up to 50 ng/ml induced bronchial hyperreactivity. But after incubation with 100 ng/ml this effect was lost and bronchial responsiveness was again comparable to the control level. The effects of IL-4 and IL-13 on bronchial reactivity were paralleled by the effects on ASMC proliferation. Fifty nanograms per milliliter of IL-4 and IL-13 increased the Ca(2+) response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca(2+) response were no longer evident. The expression of IL-13Ralpha2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13Ralpha2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca(2+) response were no longer present.


CONCLUSIONS
IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca(2+) homeostasis of ASMC. These effects are counteracted by IL-13Ralpha2. The biological significance of IL-13Ralpha2 might be a protective function by regulating IL-13- and IL-4-mediated signal transduction and thereby limiting pathological alterations in Th2-mediated inflammatory diseases.
Kellner
Julia
J
Pneumology, Medizinische Klinik-Innenstadt, Munich, Germany.
Gamarra
Fernando
F
Welsch
Ulrich
U
Jörres
Rudolf A
RA
Huber
Rudolf M
RM
Bergner
Albrecht
A
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D020013:Calcium Signaling / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009130:Muscle, Smooth / Q000378:metabolism*; D009924:Organ Culture Techniques
C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4; D000109:Acetylcholine