Date: Monday, November 9, 2020
Session Type: Poster Session D
Session Time: 9:00AM-11:00AM
Background/Purpose: Interleukin-11 (IL-11) has been shown to be associated with idiopathic pulmonary fibrosis, cardiac and kidney fibrosis. However, conflicting data shows IL-11 can be either pro- or anti-fibrotic. Scleroderma (SSc) is a fatal fibrotic disease of the vasculature, skin, and internal organs. Patients die of scarring and dysfunction of organs due to uncontrolled deposition of collagen and other extracellular matrix proteins. Our laboratory has been studying the signaling cascade mediated by caspase-1 in fibrosis. Caspase-1 activates downstream profibrotic cytokines including IL-1β, IL-18, and IL-33. We hypothesize that IL-11 may be linked to the fibrotic process in SSc through activation of caspase-1. Our purpose is to investigate the expression of IL-11 in SSc pulmonary fibroblasts and to determine the role for caspase-1 in this expression.
Methods: Fibroblasts were derived from fibrotic lung from 8 female patients with SSc with diffuse disease who developed pulmonary fibrosis. SSc patients were classified according to the ACR classification criteria for their disease. Pulmonary fibroblasts were also derived from 12 normal individuals who had died of acute events without pulmonary disease. Fibroblasts were cultured at low passage and treated with the caspase-1 inhibitor (Z-YVAD-FMK) or IL-1 receptor antagonist (IL-1RA). RNA was extracted and gene expression for IL-11, IL-11Rα1, and COL1A1 was analyzed using RT-PCR normalized to β-actin.
Results: SSc fibroblasts display a statistical trend for higher basal expression of IL-11 compared to normal fibroblasts (p=0.07) with a significantly increased expression of the IL-11 receptor, IL-11Rα1 (p=0.0002). When caspase-1 activity is inhibited with Z-YVAD-FMK, IL-11 expression is reduced (p< 0.0001), whereas receptor expression is not altered. We further show that IL-11 expression is mediated by IL-1β, as blockade of the IL-1 receptor with IL-1RA significantly reduces IL-11 (p=0.03). It did not alter IL-11Rα1 expression. Further studies show that bleomycin induces IL-11 expression in normal lung fibroblasts, and this is inhibited with either Z-YVAD-FMK (p=0.008) or IL-1RA (p=0.02). However, in our studies, we were unable to induce COL1A1 expression with IL-11 alone.
Conclusion: Our experiments show IL-11 and its receptor, IL-11Rα1, are elevated in SSc. We observed IL-11 expression is dependent on the inflammasome activation of caspase-1 as inhibition of this protein abrogates IL-11 expression. Furthermore, we identify the role for IL-1β in IL-11 expression. Further studies are warranted to determine the role for IL-11 in SSc fibrosis.
To cite this abstract in AMA style:McFalls C, Artlett C. IL-11 Expression in Systemic Sclerosis Pulmonary Fibroblasts Is Mediated by Caspase-1 [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/il-11-expression-in-systemic-sclerosis-pulmonary-fibroblasts-is-mediated-by-caspase-1/. Accessed August 1, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-11-expression-in-systemic-sclerosis-pulmonary-fibroblasts-is-mediated-by-caspase-1/