Production of Both IL-27 and IFN-γ after the Treatment with a Ligand for Invariant NK T Cells Is Responsible for the Suppression of Th2 Response and Allergic Inflammation in a Mouse Experimental Asthma Model

Abstract

Using an allergen-induced airway inflammation model, we show that an injection of α-galactosylceramide (α-GalCer), a ligand for invariant NK T (iNKT) cells, induced IL-27 and that this process is essential for the attenuation of the Th2 response. After the systemic administration of α-GalCer into the mice primed with OVA in alum, Th2 cytokine production of OVA-primed CD4+ T cells in their lymph nodes, IgG1 and IgE Ab formation, and infiltration of eosinophils in bronchoalveolar lavage after the OVA challenge were suppressed. Systemic administration of rIFN-γ into OVA-primed mice could not reproduce these effects of α-GalCer. IL-27p28 was detected both in the culture supernatant of α-GalCer-stimulated spleen cells and in the serum of the α-GalCer-treated mice, but not in the iNKT cell-deficient mice. Splenic iNKT cells produced IL-27p28 in the culture supernatant upon stimulation with PMA plus ionomycin, although the transcript of IL-27p28 in the iNKT cells was constitutively expressed regardless of the stimulation. By contrast, the transcript of IL-27EBI3 was induced in the iNKT cells upon stimulation with PMA plus ionomycin in vitro and with α-GalCer treatment in vivo, suggesting that IL-27 (p28/EBI3) could be produced by iNKT cells in an activation-dependent manner. Although repeated injections of rIL-27 did not substitute for the effects of a single injection of α-GalCer, administration of rIL-27 along with rIFN-γ reproduced in vivo effects of the α-GalCer injection. These data indicate that production of both IL-27 and IFN-γ by the α-GalCer treatment is responsible for suppression of the Th2 response and allergic inflammation.

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

“…IFN-g is generally considered a pro-rather than an antiinflammatory factor, including in the airways where it contributes to the development of antigen-induced allergic asthma when produced by eosinophils or Ag-specific CD4 1 Th1 cells [25,26]. It might be speculated that these divergent effects depending on the cellular source result from the unique capacity of iNKT cells activated by a-GC, to produce concomitantly IFN-g and IL-27 [27], a cytokine belonging to the IL-12 family [28]. In accordance with this assumption, injection of IFN-g alone failed to inhibit lung inflammation, whereas the two cytokines given together attenuated the severity of allergic asthma [27].…”

“…It might be speculated that these divergent effects depending on the cellular source result from the unique capacity of iNKT cells activated by a-GC, to produce concomitantly IFN-g and IL-27 [27], a cytokine belonging to the IL-12 family [28]. In accordance with this assumption, injection of IFN-g alone failed to inhibit lung inflammation, whereas the two cytokines given together attenuated the severity of allergic asthma [27]. It remains therefore to be determined whether iNKT cell-derived IL-27 is also required for counteracting IL-33-driven airway inflammation.…”

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

“…In addition to inducing IFN-g (18), application of R848 enhanced secretion of IL-27 in human and murine cells (27,28). Moreover, in allergen-induced airway inflammation models, secretion of IL-27 together with IFN-g was essential for attenuation of the Th2 response (29).…”

Activation of eosinophils by IL-12 family cytokine IL-27: Implications of the pleiotropic roles of IL-27 in allergic responses

“…In vivo studies are complicated and involve multi-factorial interaction, while in vitro studies simplify the direct effects of IL-27 on targeted cells. IL-27 inhibition of Th2-related diseases, such as Trichuris muris infection and OVA-induced asthma were all derived from in vivo mouse models (Artis et al 2004;Fujita et al 2009;Miyazaki et al 2005). However, no in vivo human studies of IL-27 have been reported and the stimulation effects of IL-27 on human eosinophils, monocytes and mast cells have all been derived from in vitro studies (Kalliolias and Ivashkiv 2008;Pflanz et al 2004).…”

“…In ovalbumin (OVA)-induced allergic asthma model, WSX-1−/− mice demonstrated hyperproduction of various cytokines and exhibited progressive asthmatic symptoms. IL-27 was found to inhibit Th2 cell development as well as Th2 cytokines production from polarized Th2 cells by down-regulation of transcription factor GATA-3 but up-regulation of T-bet expression simultaneously, thereby suppressing allergic responses (Artis et al 2004;Fujita et al 2009;Miyazaki et al 2005;Yoshimoto et al 2007). In addition, IL-27 repressed the development of Th17 cells and induced anti-inflammatory cytokine IL-10 to suppress IL-17-mediated inflammation (Amadi-Obi et al 2007;Awasthi et al 2007;Batten et al 2006;Fitzgerald et al 2007;Ilarregui et al 2009;Murugaiyan et al 2009;Stumhofer et al 2006Stumhofer et al , 2007Yang et al 2008).…”