Exacerbation of Experimental Allergic Asthma by Augmented Th2 Responses in WSX-1-Deficient Mice

Abstract

WSX-1 (IL-27R) is a class I cytokine receptor with homology to gp130 and IL-12 receptors and is typically expressed on CD4+ T lymphocytes. Although previous reports have clarified that IL-27/WSX-1 signaling plays critical roles in both Th1 differentiation and attenuation of cell activation and proinflammatory cytokine production during some bacterial or protozoan infections, little is known about the importance of WSX-1 in cytokine-mediated diseases of allergic origin. To this aim, we took advantage of WSX-1-deficient (WSX-1−/−) mice and induced experimental asthma, in which Th2 cytokines are central modulators of the pathology. OVA-challenged WSX-1−/− mice showed marked enhancement of airway responsiveness with goblet cell hyperplasia, pulmonary eosinophil infiltration, and increased serum IgE levels compared with wild-type mice. Production of Th2 cytokines, which are largely responsible for the pathogenesis of asthma, was augmented in the lung or in the culture supernatants of peribronchial lymph node CD4+ T cells from WSX-1−/− mice compared with those from wild-type mice. Surprisingly, IFN-γ production was also enhanced in WSX-1−/− mice, albeit at a low concentration. The cytokine overproduction, thus, seems independent from the Th1-promoting property of WSX-1. These results demonstrated that IL-27/WSX-1 also plays an important role in the down-regulation of airway hyper-reactivity and lung inflammation during the development of allergic asthma through its suppressive effect on cytokine production.

General Nature of the STAT3-Activated Anti-Inflammatory Response

“…Rather, excessive production of IL-12 and TNF-␣ is strongly linked to faster death of WSX-1 Ϫ/Ϫ mice compared with control mice. Similarly, large increases in systemic cytokines were observed in WSX-1 Ϫ/Ϫ mice infected with T. cruzi or Leishmania donovani (50, 52) and similar increases in cytokine production from T cells were also observed (53,54). These examples appear to be an IL-10-independent AIR and support the concept that the STAT3-regulated AIR could be used in diverse settings.…”

Lung CD11c+ cells from mice deficient in Epstein‐Barr virus‐induced gene 3 (EBI‐3) prevent airway hyper‐responsiveness in experimental asthma

“…In this context, a slight increase of the IgE levels in the serum of EBI-3 -/-mice was noted. This effect could be related to the defective IL-27 expression in EBI-3 -/-mice since also WSX-1 (IL-27R)-deficient mice have increased IgE levels [8]. Interestingly, adoptive transfer of DC from OVAsensitized and -challenged mice reduced AHR and induced IL-12 levels in the airways of recipient mice without changing eosinophilia, suggesting that eosinophilia is controlled by EBI-3-deficient T cells rather than DC [32].…”

“…III). It is also possible that the effect of EBI-3 on B cells is related to IL-27, as WSX-1 (IL-27R)-deficient mice have increased IgE levels in the serum [8].…”

“…It has been suggested that STAT-1 is activated through interaction with the tyrosine residue in the cytoplasmic domain of WSX-1. Furthermore, IL-27 induces expression of T-bet and IL-12Rb2 through WSX-1 signaling in wild-type naive CD4 + T cells, indicating that IL-27/WSX-1 signaling is important for the initial commitment of the Th1 responses [8,9]. Although IL-27 has been shown to positively regulate Th1 pathways, EBI-3 could have a distinct function that is not yet understood [10].…”

Tumor‐specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti‐tumor immunity

“…WSX-1 2/ 2 deficient mice developed severe immunopathology over WT mice in various experimental settings. [29][30][31][32] Suppression of Th17 differentiation is partly responsible for the anti-inflammatory effect of IL-27. 10-12 Induction of IL-10 production by activated T cells is responsible for IL-27-mediated regulation of inflammation.…”