Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation.
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.
HMS LINCS Center, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Douglas S
DS
Jones
HMS LINCS Center, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Anne P
AP
Jenney
Immunology and Inflammation, Boehringer Ingelheim, Ridgefield, Connecticut, USA.
Jennifer L
JL
Swantek
Immunology and Inflammation, Boehringer Ingelheim, Ridgefield, Connecticut, USA.|Systems Biology, Boehringer Ingelheim, Ridgefield, Connecticut, USA.
John M
http://orcid.org/0000-0002-1706-5973
JM
Burke
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Douglas A
DA
Lauffenburger
HMS LINCS Center, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Peter K
PK
Sorger
D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D013582:Synovial Fluid / Q000166:cytology*; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000008:administration & dosage; D007783:Lactones; D012118:Resorcinols
D018501:Antirheumatic Agents; D016207:Cytokines; D015025:Zearalenone; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols