Contribution of Interleukin 6 Trans Signaling In Pulmonary Fibrosis

<p>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<em> </em>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. <em>In vivo</em> 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. <em>In vitro</em> 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 <em>in vivo</em>.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Le, Thuy T

Contributors dc:contributor

• Michael R. Blackburn
• Russell Broaddus
• Sandeep Agarwal

• interleukin 6 trans signaling
• soluble IL-6R alpha
• idiopathic pulmonary fibrosis
• ADAM17
• gp130Fc
• phospho-STAT3
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/469

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1508