Role of IFN- γ in the Inhibition of the Allergic Airway Inflammation Caused by IL-12

Abstract

T-helper 2 (Th2)-like cells are thought to play a crucial role in the pathogenesis of the eosinophilic airway inflammation observed in asthma. In a murine model of allergen-induced airway eosinophilia and bronchial hyperresponsiveness (BHR), we have shown that interleukin (IL)-12 can suppress antigen-induced airway changes despite the presence of circulating specific IgE. In the present study, we investigated the role of interferon-gamma (IFN-gamma) in the inhibitory effects of IL-12 on allergic airway inflammation. Repeated daily exposure of actively immunized mice to aerosolized ovalbumin (OVA), as compared with aerosolized saline (SAL), induced a significant increase in bronchoalveolar lavage fluid (BALF) eosinophilia and OVA-specific serum IgE in both IFN-gamma-receptor-deficient (IFN-gammaR KO) and wild-type mice. As compared with placebo (PLAC), administration of recombinant murine IL-12 (rmIL-12) during the daily aerosol exposure (but not at the time of immunization) significantly inhibited BALF eosinophilia in both IFN-gammaR KO mice and wild-type controls, without influencing the production of specific IgE. In contrast, administration of rmIL-12 during the active immunization inhibited both BALF eosinophilia and specific IgE in wild-type mice as compared with littermates given PLAC; however, treatment with rmIL-12 during immunization, in comparison with PLAC, caused a significant increase in BALF eosinophilia and specific IgE in IFN-gammaR KO mice. These results demonstrate that inhibition of the allergen-induced eosinophil influx in murine airways by IL-12 is IFN-gamma-dependent during the initial sensitization, but becomes IFN-gamma-independent during the secondary response.

Mast cell–derived TNF can promote Th17 cell–dependent neutrophil recruitment in ovalbumin-challenged OTII mice

“…Notably, we also found that IFN-␥ can suppress the development of airway neutrophilia in OVA-challenged OTII mice, as has been reported in models of Th2-associated airway eosinophilia. 34 Thus, our evidence also indicates that Th1 cells can negatively regulate aspects of Th17 cell and IL-17-dependent inflammation, at least in this model system. The results obtained in our analyses of the leukocytes present after OVA challenge in the BALF specimens derived from the many different types of cytokine-, receptor-or mast cell-deficient OVA-specific TCR-expressing OTII mice investigated in this model are summarized in Table S1.…”

Interleukin‐12 as a target for modulation of the inflammatory response in asthma

“…In contrast to IL-12's effects on AHR, the inhibitory effects of IL-12 on BAL eosinophilia have been shown to be only partially IFN-y mediated (47). Such partial IFN-y dependence in these studies could have resulted from an incomplete neutralization of the cytokine in vivo with anti-IFN-y mAb.…”

“…Such partial IFN-y dependence in these studies could have resulted from an incomplete neutralization of the cytokine in vivo with anti-IFN-y mAb. However, a recent study by Brusselle et al using IFN-y receptor-deficient mice has virtually excluded this possibility (47). Interestingly, they demonstrated that while antigen-induced airway eosinophilia is largely IFN-y-independent when IL-12 is given during secondary allergen exposure, when it is given before sensitization, BAL eosinophilia is IFN-y dependent (47).…”

“…However, a recent study by Brusselle et al using IFN-y receptor-deficient mice has virtually excluded this possibility (47). Interestingly, they demonstrated that while antigen-induced airway eosinophilia is largely IFN-y-independent when IL-12 is given during secondary allergen exposure, when it is given before sensitization, BAL eosinophilia is IFN-y dependent (47). A similar finding was reported in mice infected with the nematode Nippostrongylus brasiliensis, where anti-IFN-y mAb did not affect IL-12-induced inhibition of eosinophilia during a secondary infection (38).…”

Serum interferon‐gamma/interleukin‐4 imbalance in patients with Eales' disease

“…Reciprocal regulation between Th1 and Th2 cytokines has been documented previously. [16][17][18][19] Based on the unique cytokine pattern associated with ED, we propose that TNF-a elevation might inhibit the IL-4 production and impair the Th1/Th2 balance, consequently contributing to the pathogenesis of ED. The aetiology of ED has been suggested to be multifactorial.…”