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Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung

https://doi.org/10.1016/j.jaci.2009.01.003Get rights and content

Background

Allergic asthma results from inappropriate TH2-mediated inflammation. Both IL-4 and IL-13 contribute to asthma pathogenesis, but IL-4 predominantly drives TH2 induction, whereas IL-13 is necessary and sufficient for allergen-induced airway hyperresponsiveness and goblet cell hyperplasia. Although these 2 cytokines share signaling components, the molecular mechanisms by which they mediate different phases of the allergic asthmatic response remain elusive.

Objective

We sought to clarify the role or roles of IL-4 and IL-13 in asthma-pathogenesis.

Methods

We used DNA Affymetrix microarrays to profile pulmonary gene expression in BALB/c mice inoculated intratracheally with ragweed pollen, house dust mite, IL-4, IL-13, or both cytokines. IL-13 dependence was confirmed by comparing pulmonary gene expression in house dust mite–inoculated wild-type and IL-13 knockout mice.

Results

A signature gene expression profile consisting of 23 genes was commonly induced by means of inoculation with house dust mite, ragweed pollen, or IL-4 plus IL-13. Although rIL-4 and rIL-13 treatment induced an overlapping set of genes, IL-4 uniquely induced 21 genes, half of which were interferon response genes and half of which were genes important in immunoregulation. IL-13 uniquely induced 8 genes, most of which encode proteins produced by epithelial cells.

Conclusions

IL-4 and IL-13 together account for most allergen-induced pulmonary genes. Selective IL-4 induction of IFN-γ response genes and other genes that might negatively regulate allergic inflammation could partially explain the greater importance of IL-13 in the effector phase of allergic airway disease.

Section snippets

Animals

Four-week-old female BALB/c mice were purchased from Jackson Laboratories (Bar Harbor, Me). All mice were housed under laminar flow hoods in an environmentally controlled specific pathogen-free animal facility. The studies reported conformed to the principles for laboratory animal research, as outlined by the Animal Care and Use Committee of Cincinnati Children's Hospital Medical Center.

Allergen and cytokine treatment protocols

Mice were sensitized by means of intraperitoneal injection of 150 μg of endotoxin-free ragweed pollen (RWP)

Comparison of allergen and TH2 cytokine–induced gene expression patterns

Initial experiments compared gene expression in whole lungs isolated from mice challenged with PBS, RWP, or HDM or with rIL-4, rIL-13, or rIL-4 plus rIL-13. Of the approximate 19,207 unique genes and 7,600 expressed sequence tags represented by the 45,000 probes on the array set, expression of 1,813 gene transcripts was found to be significantly different in the lungs of allergen- or cytokine-treated lungs compared with that seen in their corresponding control groups. Hierarchic cluster

Discussion

The present study used Affymetrix microarray technology to comprehensively profile gene expression in the allergic lung to gain insight into the molecular mechanisms underlying the pathogenesis of asthma and to identify novel targets for therapeutic development. Our specific objectives were to define the patterns of expression associated with allergen challenge in the mouse lung and determine the relative contribution of IL-4 and IL-13 to this pattern. To this end, we identified an “asthma

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  • Cited by (0)

    Supported by PO1 HL076383 to M.W-K. and F.D.F.; HL67736-08 (M.W-K.) and AI052099 (F.D.F.); and the CONICIT and Universidad Centroccidental Lisandro Alvarado (Venezuela) to J.S. C.C.L. has received research support from the National Institute of Allergy and Infectious Diseases.

    Disclosure of potential conflict of interest: F. D. Finkelman is a consultant for Abbott. The rest of the authors have declared that they have no conflict of interest.

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