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Division of Pulmonary Medicine, Joseph Stokes, Jr. Research Institute, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
In testing the hypothesis that
interleukin-4 receptor 
-subunit (IL-4R)-coupled signaling
mediates altered airway smooth muscle (ASM) responsiveness in the
atopic sensitized state, isolated rabbit tracheal ASM segments were
passively sensitized with immunoglobulin E (IgE) immune complexes, both
in the absence and presence of an IL-4R blocking antibody
(anti-IL-4RAb). Relative to control ASM, IgE-sensitized tissues
exhibited enhanced isometric constrictor responses to administered ACh
and attenuated relaxation responses to isoproterenol. These
proasthmatic-like effects were prevented in IgE-sensitized ASM that
were pretreated with anti-IL-4RAb. In complementary experiments,
IgE-sensitized cultured human ASM cells exhibited upregulated
expression of IL-13 mRNA and protein, whereas IL-4 expression was
undetected. Moreover, extended studies demonstrated that 1)
exogenous IL-13 administration to naïve ASM elicited augmented
contractility to ACh and impaired relaxation to isoproterenol,
2) these effects of IL-13 were prevented by pretreating the
tissues with an IL-5 receptor blocking antibody, and 3)
IL-13 administration induced upregulated mRNA expression and release of
IL-5 protein from cultured ASM cells. Collectively, these findings
provide new evidence demonstrating that the altered responsiveness of
IgE-sensitized ASM is largely attributed to activation of an intrinsic
Th2-type autocrine mechanism involving IL-13/IL-4R-coupled release
and action of IL-5 in the sensitized ASM itself.
Th2 cytokines; immunoglobulin E; atopy; asthma; interleukin-13
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