Date of Graduation
Biochemistry and Molecular Biology
Doctor of Philosophy (PhD)
Michael R. Blackburn
Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 years of diagnosis. IPF incidence and prevalence rates are increasing annually, and because the pathogenesis is unknown, there are no effective treatments available. Inhibition of interleukin 6 (IL-6) results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6 receptor alpha (mIL-6Rα), or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis and showed that protease-mediated cleavage was important in production of sL-6Rα in fibrotic lungs. In vivo neutralization of sIL-6Rα, and resulting antagonism of IL-6 trans signaling, attenuated pulmonary fibrosis in mice. Decreases in sIL-6Rα were associated with reductions in myofibroblasts, fibronectin and collagen. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. These findings suggest that IL-6 trans signaling influences events crucial in pulmonary fibrosis in vivo.
interleukin 6 trans signaling, soluble IL-6R alpha, idiopathic pulmonary fibrosis, ADAM17, gp130Fc, phospho-STAT3