The role of IL-6 in T-bet (-/-) mice in an allergic asthma model (91.10)

Abstract

IL-6 is a pleiotropic cytokine which induces Th2 type cells. IL-6 binds to IL-6R alpha chain and then induces gp130 dimerization resulting in the intracellular activation of Janus kinase and signal transducers and activators of transcription (STAT) pathways. We previously demonstrated that patients affected by allergic asthma have an increased level of soluble IL-6R which correlates with Th2 CD4+ T-cells in their airways. In a murine model of this disease, we also demonstrated that IL-6 inhibits the development of T-regulatory cells (Tregs) and local blockade of IL-6R resulted in the expansion of Tregs as well as Th1 cells in the lung. T-bet is a Th1-specific transcriptional factor. Mice lacking T-bet show increased asthmatic symptoms. We thus want to study the influence of T-bet on IL-6 mediated inhibition of Tregs. To this aim an antibody against IL-6R was applied to T-bet deficient mice (T-bet (-/-)) during allergen challenge. In preliminary studies we found that local blockade of IL-6R in T-bet (-/-) mice resulted in a reduced AHR and decreased lung eosinophilia. Furthermore we observed selective expansion of the CD4+ CD25+ Foxp3+ Tregs in the draining lymph-nodes taken from anti IL-6R-antibody treated T-bet (-/-) mice, compared to T-bet (-/-) untreated mice. These results suggest that local blockade of IL-6R in the absence of T-bet in allergic asthma could result in amelioration of the disease hallmarks because of inducing Tregs in the local draining lymph nodes.