IL-6 overexpression triggers inflammation through its only relevant receptor IL-6R

Abstract IL-6 is a pleiotropic cytokine that regulates development and function of variety immune cells. Here we used a novel mouse strain in which IL-6 can be overexpressed in a Cre-dependent manner and show that mice with CD11c-Cre mediated IL-6 overexpression succumb from systemic inflammation. High levels of IL-6 perturbed B and T cell development in primary lymphoid organs, bone marrow and thymus. Interestingly, IL-6-triggered inflammation promoted expansion of both Th17 and Treg cells, two cell types known for their reciprocal developmental requirements. However, the most dramatic increase was noted for myeloid cells, mostly neutrophils, which invaded spleen, thymus and blood of mice with IL-6 overexpression. Observed systemic inflammation ultimately led to mice mortality within 11 weeks of age. Mechanistically, IL-6 mediates its biological functions strictly through binding to IL-6R alpha chain followed by recruitment of the signal transducer gp130. Previously, an alternative pathway was suggested in which IL-6 can utilize CD5 to signal via gp130. However, when IL-6R was deleted in mice with IL-6 overexpression these mice were completely protected from IL-6- triggered pathology and fully phenocopied IL-6R deficient mice. In fact, IL-6R deficiency prevented downstream activation of STAT3 in response to IL-6. Together, our data suggest that IL-6R is the only biological relevant receptor for IL-6 in mice.