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Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation

Author(s)
Jenney, Anne P; Swantek, Jennifer L; Burke, John M; Sorger, Peter K; Jones II, Douglas S.; Lauffenburger, Douglas A; ... Show more Show less
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Abstract
Activation of synovial fibroblasts (SFs) contributes to rheumatoid arthritis (RA) by damaging synovial membranes and generating inflammatory cytokines that recruit immune cells to the joint. In this paper we profile cytokine secretion by primary human SFs from healthy tissues and from donors with RA and show that SF activation by TNF, IL-1α, and polyinosinic-polycytidylic acid (Poly(I:C)) cause secretion of multiple cytokines found at high levels in RA synovial fluids. We used interaction multiple linear regression to quantify therapeutic and countertherapeutic drug effects across activators and donors and found that the ability of drugs to block SF activation was strongly dependent on the identity of the activating cytokine. (5z)-7-oxozeaenol (5ZO), a preclinical drug that targets transforming growth factor-β-activated kinase 1 (TAK1), was more effective at blocking SF activation across all contexts than the approved drug tofacitinib, which supports the development of molecules similar to 5ZO for use as RA therapeutics.
Date issued
2016-10
URI
http://hdl.handle.net/1721.1/117697
Department
Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology
Journal
Nature Chemical Biology
Publisher
Springer Nature
Citation
Jones, Douglas S., et al. “Profiling Drugs for Rheumatoid Arthritis That Inhibit Synovial Fibroblast Activation.” Nature Chemical Biology, vol. 13, no. 1, Jan. 2017, pp. 38–45.
Version: Author's final manuscript
ISSN
1552-4450
1552-4469

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