Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity

Abstract

Airway hyperresponsiveness to a variety of specific and nonspecific stimuli is a cardinal feature of asthma, which affects nearly 10% of the population in industrialized countries. Eosinophilic pulmonary inflammation, eosinophil-derived products, as well as Th2 cytokines IL-13, IL-4, and IL-5, have been associated with the development of airway hyperreactivity (AHR), but the specific immunological basis underlying the development of AHR remains controversial. Herein we show that mice with targeted deletion of IL-13 failed to develop allergen-induced AHR, despite the presence of vigorous Th2-biased, eosinophilic pulmonary inflammation. However, AHR was restored in IL-13−/− mice by the administration of recombinant IL-13. Moreover, adoptive transfer of OVA-specific Th2 cells generated from TCR-transgenic IL-13−/− mice failed to induce AHR in recipient SCID mice, although such IL-13−/− Th2 cells produced high levels of IL-4 and IL-5 and induced significant airway inflammation. These studies definitively demonstrate that IL-13 is necessary and sufficient for the induction of AHR and that eosinophilic airway inflammation in the absence of IL-13 is inadequate for the induction of AHR. Therefore, treatment of human asthma with antagonists of IL-13 may be very effective.

Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

“…Histopathological analysis revealed a significant decrease in goblet cells metaplasia in MIF -/-compared to WT mice. It is well established that metaplasia of goblet cells and the hypersecretion of mucin in asthma are dependent on IL-13, chemokines and leukotrienes [8,9,[40][41][42]. The lower levels of these inflammatory mediators in the lung of MIF -/-mice might constitute an important cause for the observed decreased mucus production in these animals.…”

“…These changes occur despite a robust antigen-specific Th2 response observed by increased antigen-specific IgE concentrations, IL-4 production and lymph node cell proliferation. Treatment of immunized BALB/c mice with anti-MIF, exclusively during the challenge phase, inhibited the induction of AHR and eosinophil infiltration without affecting the production of inflammatory mediators such as IL-13, considered essential to the development of AHR and lung allergic inflammation [8,9,39,40]. Thus, the lack of AHR and eosinophilic inflammation in MIF -/-mice and in BALB/c mice treated with anti-MIF supports and extends an emerging concept that MIF is essential to allergic asthma.…”

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

“…50 In experimental asthma models, airway hyperreactivity accompanied by high levels of IL-4 and IL-5 secretion can be induced in intact but not IL-13À/À mice. 51,52 Sensitized animals can be protected by treatment with IL-13Ra-chain constructs, 53 and although the IL-4Ra-chain may be involved, this is disputed. 46,49 Mice whose Th1 system is crippled by the genetic disruption of T-bet expression develop spontaneous asthma-like disease, which is accompanied by high numbers of CD44 and CD69 bright CD4 þ T cells; again, this condition can be ameliorated by the direct blockade of IL-13.…”

Gene expression analysis in a murine model of allergic asthma reveals overlapping disease and therapy dependent pathways in the lung

“…The lack of increase in Ig mRNA concentration following pulmonary mIL-13 administration may reflect timing or more likely lack of antigen-specific signaling supporting Bcell expansion and trafficking. 31 Pulmonary administration of mIL-13 also resulted in identification of additional genes within the OVA challenge functional categories and additional functional categories. We view the expanded gene set measured in IL-13-treated lungs as a reflection of an increased strength of signal mediated by intratracheal cytokine instillation.…”