Background/Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 2.5 millions of Americans. Several cytokines are involved in RA pathogenesis and may serve as potential therapeutic targets. IL-11, a member of the IL-6 family of cytokines, plays important roles in a number of physiological functions. However, pathological overexpression of IL-11 in autoimmune diseases, including RA, has also been described. Despite its overexpression in RA joint, data from studies describing the role of IL-11 in RA are controversial. In phase I/II studies, treatment with IL-11 did not affect disease activity, while others established that patients in remission had lower serum IL-11 levels that correlated with disease activity score (DAS)28 improvement. To address these controversies, we sought to elucidate the expression pattern, and functional role of IL-11 and IL-11R in RA synovitis.

Methods:

IL-11 and IL-11Ra expressions were determined in RA tissues and cells (RA subjects meet the 1987 Revised Criteria for RA Classification) using immunohistochemistry and ELISA. IL-11 effector functions on RA fibroblasts and endothelial cells were studied using scratch assay and endothelial cell migration and tube formation.

Results: We found that IL-11 levels were significantly higher in RA synovial fluid (SF) compared to osteoarthritis (OA) SF (47 fold) and plasma from RA (19 fold), OA (75 fold) and normal (NL) (18 fold) volunteers. The expression of IL-11 was significantly elevated (2 fold) in the sublining endothelial cells of RA relative to NL synovial tissues (STs). In addition, the expression of IL-11 was higher (2.5 fold) in the lining fibroblasts of RA compared to OA STs. Both histology and Western blot analysis demonstrated that IL-11Ra is expressed in RA ST fibroblasts and endothelial cells but not in NL or RA macrophages. IL-11 expression was enhanced in RA ST fibroblasts primarily by IL-1b; however, expression in endothelial and RA monocytes and macrophages was only promoted by RA SF. Employing RA fibroblasts based scratch assay, we observed that IL-11 could dose dependently promote RA fibroblast proliferation through IL-11Ra starting at 100 ng/ml, as the proliferative effect was abrogated in the presence of IL-11Ra-Fc chimeric protein. In addition, IL-11 induced synovial fibroblasts to release IL-8 and VEGF which contributed to endothelial cell transmigration and tube formation. Furthermore, IL-11, starting at a dose of 1 ng/ml, induced endothelial cell migration (13-75 fold) and tube formation (19 fold) indicating that IL-11 can contribute to angiogenesis at a physiologically relevant concentration (up to 3.7 ng/ml is expressed in RA SF). The addition of the soluble IL-11Ra-Fc chimeric protein reduced the IL-11 induced endothelial cell migration by 50% and abrogated the tube formation driven by RA SF suggesting that the IL-11 pro-angiogenic effect is mediated through IL-11Ra.

Conclusion: The binding of IL-11 to IL-11Ra on RA fibroblasts and endothelial cells promoted cell proliferation and angiogenesis respectively. Therefore, our study suggests that IL-11 may be responsible for synovial fibroblast hyperplasia and it further potentiates disease severity by increasing the invasion of blood vessels into the RA pannus.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-pathogenic-functions-of-il-11-on-ra-joint-fibroblasts-and-endothelial-cells/