Requirement for IL-13 independently of IL-4 in experimental asthma

Abstract

The pathogenesis of asthma reflects, in part, the activity of T cell cytokines. Murine models support participation of interleukin-4 (IL-4) and the IL-4 receptor in asthma. Selective neutralization of IL-13, a cytokine related to IL-4 that also binds to the alpha chain of the IL-4 receptor, ameliorated the asthma phenotype, including airway hyperresponsiveness, eosinophil recruitment, and mucus overproduction. Administration of either IL-13 or IL-4 conferred an asthma-like phenotype to nonimmunized T cell-deficient mice by an IL-4 receptor alpha chain-dependent pathway. This pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL-4 receptor.

Fig. 1

PAS-stained histologic sections of murine lungs. Arrowheads point to goblet cells within the respiratory epithelium. (A) Wild-type mice were primed with OVA and challenged with PBS intranasally. (B) Wild-type mice were administered IL-13 intranasally. (C) IL-4–deficient and (D) IL-4Rα–deficient mice were primed with OVA and challenged with OVA intranasally. Wild-type mice were primed with OVA and challenged intranasally with (E) OVA and human Fc control protein or with (F) OVA and IL-13R-Fc. Note the marked reduction in goblet cells in (D) and (F).

Fig. 2

Effect of neutralization of IL-13. Primed wild-type mice were administered intranasally human immunoglobulin (Ig control), Ig control and OVA, or IL-13R-Fc and OVA as indicated by (+). Data for (A) AHR, (B) goblet cell score, and numbers of (C) eosinophils and (D) neutrophils in the BAL fluid are plotted as means ± SEM. *P < 0.05 relative to PBS and Ig control–treated mice; †P < 0.05 relative to OVA and Ig control–treated mice. Data are representative of at least two comparable experiments with four to eight mice per group.

Fig. 3

Effect of recombinant IL-4 and IL-13. Wild-type (WT), RAG1-deficient (RAG1^−/−), and IL-4Rα–deficient (IL-4Rα^−/−) mice were administered IL-4, IL-13, or control protein intranasally. Data for (A) AHR, (B) goblet cell score, and numbers of (C) eosinophils and (D) neutrophils in the BAL fluid are plotted as means ± SEM. *P < 0.05 relative to mice receiving control protein. Data are representative of at least two comparable experiments with four to eight mice per group.