Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression.
OBJECTIVE
Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP.


METHODS
The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP.


RESULTS
TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation.


CONCLUSIONS
The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
E A
EA
Ross
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
A J
AJ
Naylor
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
J D
JD
O'Neil
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
T
T
Crowley
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
M L
ML
Ridley
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
J
J
Crowe
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
T
T
Smallie
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
T J
TJ
Tang
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
J D
JD
Turner
William Harvey Research Institute, QMUL, London, UK.
L V
LV
Norling
Division of Rheumatology, Northwestern University, Chicago, Illinois, USA.
S
S
Dominguez
Division of Rheumatology, Northwestern University, Chicago, Illinois, USA.
H
H
Perlman
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.
N M
NM
Verrills
Division of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece.
G
G
Kollias
Cognosci Inc., Research Triangle Park, North Carolina, USA.
M P
MP
Vitek
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
A
A
Filer
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
C D
CD
Buckley
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
J L
JL
Dean
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
A R
AR
Clark
D000605:Amino Alcohols / Q000627:therapeutic use; D000818:Animals; D001057:Apolipoproteins E / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C000611333:AAL(S) compound; D000605:Amino Alcohols; D001057:Apolipoproteins E; C524548:COG1410; D016207:Cytokines; D012333:RNA, Messenger; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2
Cytokines; Fibroblasts; Inflammation; Rheumatoid Arthritis; TNF-alpha