IL-4 Promotes Airway Eosinophilia by Suppressing IFN-γ Production: Defining a Novel Role for IFN-γ in the Regulation of Allergic Airway Inflammation

IL-4 and IL-13 play key roles in Th2 immunity and asthma pathogenesis. Although the function of these cytokines is partially linked through their shared use of IL-4Rα for signaling, the interplay between these cytokines in the development of memory Th2 responses is not well delineated. In this investigation, we show that both IL-4 and IL-13 influence the maturation of dendritic cells (DC) in the lung and their ability to regulate secretion of IFN-γ and Th2 cytokines by memory CD4+ T cells. Cocultures of wild-type T cells with pulmonary DC from allergic, cytokine-deficient mice demonstrated that IL-4 enhanced the capacity of DC to stimulate T cell secretion of Th2 cytokines, whereas IL-13 enhanced the capacity of DC to suppress T cell secretion of IFN-γ. Because IL-4Rα is critical for IL-4 and IL-13 signaling, we also determined how variants of IL-4Rα influenced immune cell function. T cells derived from allergic mice expressing a high-affinity IL-4Rα variant produced higher levels of IL-5 and IL-13 compared with T cells derived from allergic mice expressing a low-affinity IL-4Rα variant. Although DC expressing different IL-4Rα variants did not differ in their capacity to influence Th2 cytokine production, they varied in their capacity to inhibit IFN-γ production by T cells. Thus, IL-4 and IL-13 differentially regulate DC function and the way these cells regulate T cells. The affinity of IL-4Rα also appears to be a determinant in the balance between Th2 and IFN-γ responses and thus the severity of allergic disease.

Section: Discussionmentioning

confidence: 99%

Comparative Roles of IL-4, IL-13, and IL-4Rα in Dendritic Cell Maturation and CD4+ Th2 Cell Function

Webb

Cai

Matthaei

et al. 2007

“…It has been previously demonstrated that modulation of Th2 cytokines has a significant effect on an allergen-induced inflammatory response (29,30,37,40) and that Th1-and Th2-type responses are antagonistic to each other. Introduction of Th1-type mediators, such as IL-12 and IFN-␥, into an allergic response has been shown to decrease the severity of that inflammatory response (25,26,28,31).…”

Section: Discussionmentioning

confidence: 99%

“…It has been established that Th1 and Th2 responses are antagonistic to each other (25)(26)(27)(28)(29). Administration of IFN-␥, a Th1-type cytokine, into the airways of allergic mice has been demonstrated to reduce the severity of the Th2-type response and attenuate asthma-like responses (30,31).…”

mentioning

confidence: 99%

Regulation of Cockroach Antigen-Induced Allergic Airway Hyperreactivity by the CXCR3 Ligand CXCL9

Thomas

Kunkel

Lukacs

2004

Allergic airway disease is characterized by a robust lymphocytic infiltrate, elaboration of Th2-type inflammatory mediators, pulmonary eosinophil accumulation, and airway hyperreactivity. The CXCR3 ligands, CXCL9 (monokine induced by IFN-γ) and CXCL10 (IFN-inducible protein, 10 kDa), are IFN-γ-inducible, Th1-type chemokines. As CXCL10 has been previously shown to participate in the modulation of allergic inflammation, we were interested in investigating the possible role that CXCL9 may play in this inflammatory response. Expression of CXCL9 was primarily identified in airway epithelial cells by immunohistochemical staining. Airway neutralization of CXCL9 at the time of allergen challenge significantly increased airway hyperreactivity, airway eosinophil accumulation, and IL-4 levels in the bronchoalveolar lavage while significantly decreasing airway levels of IL-12. In contrast, introduction of exogenous CXCL9 into the airway at the time of allergen challenge dramatically reduced airway hyper-reactivity and eosinophil accumulation. Moreover, pulmonary levels of IL-4 were significantly reduced, whereas levels of IL-12 were significantly increased, with exogenous CXCL9 treatment. In lymphocytes restimulated with CXCL9 and allergen in vitro, CXCL9 down-regulated IL-4 expression and up-regulated IFN-γ expression, suggesting that CXCL9 is able to direct activated lymphocytes toward a Th1-type phenotype. Additionally, CXCL9 was shown to inhibit CC chemokine ligand 11-induced eosinophil chemotaxis in in vitro assays. Taken together, our results demonstrate that the CXCR3 ligand CXCL9 is involved in regulation of the allergic response in the lung by regulation of lymphocyte activation and eosinophil recruitment.

“…It has been established that Th1 and Th2 responses are antagonistic to each other (22)(23)(24)(25)(26). Administration of IFN-␥ into the airways of allergic mice has been demonstrated to reduce the severity of the Th2 type response and attenuate asthma-like responses (27,28).…”

mentioning

confidence: 99%

Differential Role of IFN-γ-Inducible Protein 10 kDa in a Cockroach Antigen-Induced Model of Allergic Airway Hyperreactivity: Systemic Versus Local Effects

Thomas

Kunkel

Lukacs

2002

The ability of IFN-γ to antagonize established Th2 type allergic responses is well documented. To investigate the role of IFN-γ-inducible protein 10 kDa (IP10) in the allergic response, we chose to investigate the effect of IP10 neutralization on an established Th2 response. Systemic neutralization of IP10 at the time of allergen challenge increased airway hyperreactivity as well as airway eosinophil accumulation. Interestingly, IFN-γ levels were markedly reduced in both the lung and peripheral lymph node following IP10 neutralization. Furthermore, the number of CXCR3+CD4+ T cells was decreased in the peripheral lymph node following neutralization of IP10. Introduction of exogenous IP10 into the airway at the time of allergen challenge also dramatically increased eosinophil accumulation in the airway. Protein levels of IL-4, IL-5, and IL-13 were significantly increased in the lung following exogenous airway administration of IP10 with allergen. Interestingly, airway hyperreactivity was significantly decreased at early time points following concurrent IP10 and allergen challenge but rebounded at 24 and 48 h post allergen challenge. Although IP10 may initially be acting locally to dampen the allergic response, its ability to recruit eosinophils may ultimately supersede any immunomodulatory effect it may have in an established allergic response. These results suggest that while systemic levels of IP10 are beneficial in controlling the allergic response, possibly by regulating cellular trafficking in the lymph node, local administration of exogenous IP10 into an established allergic response may be detrimental.