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Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Nat+Chem+Biol 2017 ; 13 (1): 38-45 Nephropedia Template TP
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Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation #MMPMID27820799
Jones DS; Jenney AP; Swantek JL; Burke JM; Lauffenburger DA; Sorger PK
Nat Chem Biol 2017[Jan]; 13 (1): 38-45 PMID27820799show ga
Activation of synovial fibroblasts (SF) 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 SF from normal and RA donors and show that SF activation by TNF?, IL?1?, and Poly(I:C) causes secretion of multiple cytokines found at high levels in RA synovial fluids. We use interaction multi-linear regression to quantify therapeutic and counter?therapeutic drug effects across activators and patient donors and find that the ability of drugs to block SF activation is strongly dependent on the identity of the activating cytokine. (5z)?7?oxozeaenol (5ZO), a pre?clinical drug whose primary target is transforming growth factor ??associated kinase 1 (TAK1), is more effective at blocking SF activation across all contexts than the approved drug tofacitinib, arguing for development of molecules similar to 5ZO as RA therapeutics.