IL-12 Contributes to Allergen-Induced Airway Inflammation in Experimental Asthma

Abstract

Lack of sufficient IL-12 production has been suggested to be one of the basic underlying mechanisms in atopy, but a potential role of IL-12 in established allergic airway disease remains unclear. We took advantage of a mouse model of experimental asthma to study the role of IL-12 during the development of bronchial inflammation. Administration of anti-IL-12p35 or anti-IL-12p40 mAb to previously OVA-sensitized BALB/c mice concomitantly with exposure to nebulized OVA, abolished both the development of bronchial hyperresponsiveness to metacholine as well as the eosinophilia in bronchoalveolar lavage fluid and peripheral blood. Anti-IL-12 treatment reduced CD4+ T cell numbers and IL-4, IL-5, and IL-13 levels in the bronchoalveolar lavage fluid and the mRNA expression of IL-10, eotaxin, RANTES, MCP-1, and VCAM-1 in the lung. Anti-IL-12p35 treatment failed to show these effects in IFN-γ knockout mice pointing to the essential role of IFN-γ in IL-12-induced effects. Neutralization of IL-12 during the sensitization process aggravated the subsequent development of allergic airway inflammation. These data together with recent information on the role of dendritic cells in both the sensitization and effector phase of allergic respiratory diseases demonstrate a dual role of IL-12. Whereas IL-12 counteracts Th2 sensitization, it contributes to full-blown allergic airway disease upon airway allergen exposure in the postsensitization phase, with enhanced recruitment of CD4+ T cells and eosinophils and with up-regulation of Th2 cytokines, chemokines, and VCAM-1. IFN-γ-producing cells or cells dependent on IFN-γ activity, play a major role in this unexpected proinflammatory effect of IL-12 in allergic airway disease.

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…In addition to the inhibition of OVA-induced pulmonary infiltration of eosinophils, lymphocytes and neutrophils, and increase in Th2 cytokine IL-4, IL-5 and IL-13 in the allergic airway (Ho et al 2012;Cheng et al 2011), artesunate was able to reduce the BALF level of a broad range of pro-inflammatory cytokines including IL-17, MCP-1, IL-12 p(40) and G-CSF. IL-12 p(40) has been linked to the full-blown asthma phenotype (Meyts et al 2006) and G-CSF is a major survival factor for neutrophils (Dai et al 2012). We have reported that BALF levels of sterols such as cholesterol, cholic acid and cortol declined in asthma model .…”

Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice

“…Indeed, while some reports showed that administration of recombinant IL-12 ameliorates allergic airway inflammation (43), studies in IL-12-deficient mice showed that IL-12 deficiency does not alter the Th1/Th2 balance after secondary allergen exposure (44). Finally, a more recent report, in which neutralizing monoclonal antibodies against IL-12 were used, proposed an aggravating effect of IL-12 during allergen exposure (45). This shows how controversial the role of IL-12 remains and even suggests that inhibition of IL-12 production by lung DCs could be one of the mechanisms by which IMs prevent Th2 responses in the airways.…”

FcαRI-Mediated Inhibition of IL-12 Production and Priming by IFN-γ of Human Monocytes and Dendritic Cells

“…This might also be relevant to asthma, for which a dual role for IL-12 was demonstrated in a murine model (37). It was shown that, despite the fact that IL-12 counteracts Th2 responses during allergen sensitization, it can enhance, on further allergen exposure, the recruitment of CD4 + T cells and granulocytes, as well as Th2 cytokines and chemokines; this unexpected proallergic role of IL-12 was not observed in IFN-g-deleted mice.…”