Interleukin-13: Central Mediator of Allergic Asthma

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Science  18 Dec 1998:
Vol. 282, Issue 5397, pp. 2258-2261
DOI: 10.1126/science.282.5397.2258


The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4+ T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.

Recent decades have brought dramatic increases in the prevalence and severity of allergic asthma. In the United States, 15 million people are currently thought to suffer from the disorder (1). Allergic asthma is characterized by airway hyperresponsiveness (AHR) to a variety of specific and nonspecific stimuli, chronic pulmonary eosinophilia, elevated serum immunoglobulin E (IgE), and excessive airway mucus production (2). The pathophysiology of asthma is thought to be mediated by CD4+T lymphocytes producing a type 2 cytokine profile: (i) CD4+T cells are necessary for the induction of allergic asthma in murine models; (ii) CD4+ T cells producing type 2 cytokines undergo expansion in these models and in patients with allergic asthma; and (iii) the amount of type 2 cytokines is increased in the airway tissues of asthmatics and animal models (3–5). The circumstantial evidence for the importance of IL-4 and IL-5, which are paradigmatic type 2 cytokines, has been compelling (6–8). However, although an antibody-mediated blockade of IL-4 during allergen sensitization ablates the development of allergic asthma, a similar blockade of IL-4 before or during an antigen challenge inhibits neither allergic inflammation nor AHR (9). Thus, IL-4 generates T helper cell 2 (TH2) deviation in these models (10) but is not necessary for the expression of allergic asthma. The CD4+ T cell–derived factor or factors that mediate allergic asthma remain elusive.

IL-13 is a TH2 cytokine that binds to the α chain of the IL-4 receptor (11). We therefore examined the role of IL-13 in allergic asthma. A well-characterized murine model of allergic asthma was used, in which allergen exposure results in AHR, pulmonary eosinophilia, increases in antigen-specific serum IgE amounts, and increases in airway epithelial mucus content (12). Male A/J mice were immunized intraperitoneally and were subsequently challenged intratracheally with soluble ovalbumin (OVA); the allergic phenotype was assessed 4 days after the antigen challenge (13). Blockade of IL-13 was performed by the systemic administration of a soluble IL-13α2-IgGFc fusion protein (sIL-13Rα2-Fc), which specifically binds to and neutralizes IL-13, 24 hours before subsequent intratracheal allergen challenges (14). Antigen challenge of allergen-immunized mice resulted in significant increases in airway responsiveness to acetylcholine (15) (Fig. 1A). Blockade of IL-13 resulted in a complete reversal of such allergen-induced AHR; thus, IL-13 is necessary for the expression of AHR in this model. The ability of IL-13 ablation to reverse AHR after the full development of the phenotype of allergic asthma contrasts with the inability of IL-4 ablation to accomplish such a reversal. The mechanism underlying the effectiveness of IL-4Rα blockade in reversing allergen-induced AHR (12) may be the inhibition of IL-13–mediated processes, which is consistent with the fact that Stat6 activation is downstream of IL-4Rα–mediated signaling for both cytokines. IL-13 is probably the primary CD4+ T cell–derived factor responsible for allergen-induced AHR.

Figure 1

Reversal of allergen-induced AHR by the in vivo blockade of IL-13. Ten days after the initial intratracheal challenge, OVA- and PBS-immunized mice were again challenged intratracheally with either OVA or PBS. Mice were given sIL-13Rα2-Fc (400 μg) or an equivalent amount of control human Ig (Hu-Ig) by intraperitoneal injection on days –1, 0, +1, and +3 of the secondary antigen challenge. The allergic phenotype was assessed 4 days after the PBS or OVA challenge. (A) AHR to the acetylcholine challenge, defined by the time-integrated rise in peak airway pressure [airway-pressure-time index (APTI) in centimeters of H2O × seconds]. (B) Inflammatory cell composition of BAL fluids. Cell differential percentages were determined by light microscopic evaluation of cytospin preparations. Data are expressed as absolute numbers of cells. (C) OVA-specific serum IgE concentrations. In (A) through (C), the results are means ± SEM (error bars) of 8 to 10 animals per group and are representative of two independent experiments. *P < 0.05, compared with the respective PBS control groups; **P < 0.05, compared to the OVA+Hu-Ig group [one-way analysis of variance (ANOVA) followed by Fisher's least significant difference test for multiple comparisons].

To evaluate the candidate mechanisms underlying IL-13–dependent expression of AHR, we characterized known allergic effector cascades. Eosinophils have been implicated as primary effector cells in asthma and asthmatic AHR (16), but the inhibition of IL-13 before repeat antigen provocation did not significantly affect allergen-induced pulmonary eosinophilia (17) (Fig. 1B). To assess the relevance of IgE-mediated pathways, we measured OVA-specific serum IgE (18). OVA-specific IgE was observed in OVA-sensitized and OVA-challenged mice, whereas no antigen-specific antibody was detected in phosphate-buffered saline (PBS)–immunized and PBS-challenged mice (Fig. 1C). Blockade of IL-13 did not alter OVA-specific IgE concentrations—a lack of suppression that is likely due to the fact that the IL-13 blockade occurred after initial antigen priming and antibody formation. Nonetheless, these results show that AHR is not dependent on IgE production in this model, which is consistent with a report that allergic AHR develops normally in IgE-deficient mice (19).

In congruence with the pathology of human asthma, allergic asthma in murine models is associated with a substantial increase in the mucus content of the airway epithelium (7, 12). Mucus hypersecretion is particularly profound in autopsy specimens from patients who die of acute asthma attacks (20). Blockade of IL-13 reverses allergen-induced increases in mucus-containing cells in the airways (Fig. 2), demonstrating that allergen-induced increases in airway mucus content are dependent on IL-13. IL-4 has also been implicated in this process, because IL-4 transgenic mice display goblet-cell hyperplasia in the absence of antigen sensitization (7). However, the transfer of TH2 clones from IL-4–deficient mice into murine airways induces mucus overproduction (21), which suggests that the immunoregulatory role of IL-4 should be carefully differentiated from its role as an effector molecule.

Figure 2

Effects of the IL-13 blockade on allergen-driven increases in mucus-containing cells in the airway epithelium. Lung sections (four per experimental group and four sections per animal) were fixed in formalin; cut into 10-μm sections; and stained with hematoxylin, eosin, and periodic acid–Schiff. Representative sections are shown. (A) PBS+Hu-Ig section showing PBS-immunized and PBS-challenged controls and few mucus-containing cells. (B) OVA+Hu-Ig section showing allergen-induced increases in interstitial inflammatory cells and increases in the number of goblet cells containing mucus. (C) OVA+sIL-13Rα2-Fc section showing the inhibitory effect of the IL-13 blockade on allergen-induced mucus production in goblet cells. These data are representative of two independent experiments.

If IL-13 is necessary for the expression of allergic AHR, is it sufficient to induce it? The daily administration of recombinant IL-13 (rIL-13) to the airways of naı̈ve (unimmunized) mice induced AHR, demonstrating that increases in IL-13 activity were sufficient to induce AHR (Fig. 3A) (22). AHR developed within 72 hours from the start of rIL-13 administration. A significant influx of eosinophils into bronchoalveolar lavage (BAL) fluid was observed soon after rIL-13 administration; however, pulmonary eosinophilia was not observed at the time of expression of AHR (Fig. 3B). Although the importance of the time course of eosinophil influx remains unclear, it suggests that IL-13 alone may be sufficient to initiate eosinophilic infiltration of the airways, perhaps through its ability to up-regulate chemokine expression (23). Airway administration of rIL-13 also resulted in a time-dependent increase in total serum IgE (Fig. 3C) (24), which is in line with the ability of IL-13 to regulate IgE synthesis (25). Increases in serum IgE were independent of any immunization with allergen; these findings are consistent with the observation that the human asthmatic phenotype correlates better with total, rather than allergen-specific, serum IgE concentrations (26). As predicted from our IL-13 inhibition studies, the administration of rIL-13 induced an increase in airway mucus production (Fig. 3D) (27).

Figure 3

IL-13 induction of airway hyperreactivity. Naı̈ve mice were given murine rIL-13 (5 μg per mouse in a total volume of 50 μl) or PBS daily by intratracheal instillation. Twenty-four and 72 hours after the last treatment, (A) AHR, (B) BAL eosinophil numbers, and (C) serum total IgE concentrations were determined; (D) the mucus score was determined 72 hours after treatment. In (A) through (D), the results are means ± SEM (error bars) of 7 to 10 animals per group and are representative of three independent experiments. *P < 0.05, compared to the PBS group (Student's ttest).

Although IL-13 thus appears capable of inducing the entire allergic asthmatic phenotype, the results of the IL-13 blockade experiments clearly show that IL-13–dependent AHR occurs by mechanisms that are independent of IgE and eosinophils in this model. The exact mechanism or mechanisms by which IL-13 induces AHR are currently unknown. The delayed time course for AHR induction suggests that IL-13 does not directly cause airway smooth muscle constriction. Reasonable hypotheses include direct time-dependent alterations in smooth muscle function (IL-13 receptors have yet to be demonstrated on airway smooth muscle) and indirect effects that are achieved through mediators released by surrounding cells. Although recent studies have suggested a possible role for sensory neuron–derived tachykinins in AHR, preliminary studies in our laboratory do not support a role for these neuropeptides in IL-13–induced AHR (28).

Our data demonstrate a critical role for IL-13 in the expression of murine asthma and suggest that, although IL-4 may be of immunoregulatory importance, IL-4 is not a prime effector molecule. These findings may be relevant to human asthma. Overexpression of IL-4 is predominantly found in the airways of allergic asthmatics, whereas significant elevations in IL-13 expression are found in the airways of patients with both allergic and nonallergic asthma (4, 29). Human asthma has been linked to a region of chromosome 5q, which contains the genes for both IL-4 and IL-13 (30). Although polymorphisms in the IL-13 gene have yet to be examined, polymorphisms in the IL-4 gene are well-described (31). No significant correlations between such polymorphisms and the asthmatic phenotype have been found; however, a gain-of-function mutation in IL-4Rα was recently shown to be associated with asthma (32). These insights into the immunopathogenesis of allergic asthma should provide direction for the development of therapeutics for this increasingly prevalent disease.

  • * To whom correspondence should be addressed. E-mail: mkarp{at}


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