GLEPP1/protein-tyrosine phosphatase phi inhibitors block chemotaxis in vitro and in vivo and improve murine ulcerative colitis.
We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase . Two previously described GLEPP1 substrates, paxillin and Syk, are both required for cytoskeletal rearrangement and cellular motility of leukocytes in chemotaxis. We show here that GLEPP1 inhibitors prevent dephosphorylation of Syk1 and paxillin in resting cells and block primary human monocyte and mouse bone marrow-derived macrophage chemotaxis in a gradient of monocyte chemotactic protein-1. In mice, the GLEPP1 inhibitors also reduce thioglycolate-induced peritoneal chemotaxis of neutrophils, lymphocytes, and macrophages. In murine disease models, the GLEPP1 inhibitors significantly reduce severity of contact hypersensitivity, a model for allergic dermatitis, and dextran sulfate sodium-induced ulcerative colitis, a model for inflammatory bowel disease. Taken together, our data provide confirmation that GLEPP1 plays an important role in controlling chemotaxis of multiple types of leukocytes and that pharmacological inhibition of this phosphatase may have therapeutic use.
Gobert
Rosanna Pescini
RP
Merck Serono International, 9 Chemin des Mines, 1211 Geneva, Switzerland.
van den Eijnden
Monique
M
Szyndralewiez
Cedric
C
Jorand-Lebrun
Catherine
C
Swinnen
Dominique
D
Chen
Linfeng
L
Gillieron
Corine
C
Pixley
Fiona
F
Juillard
Pierre
P
Gerber
Patrick
P
Johnson-Léger
Caroline
C
Halazy
Serge
S
Camps
Montserrat
M
Bombrun
Agnes
A
Shipp
Margaret
M
Vitte
Pierre-Alain
PA
Ardissone
Vittoria
V
Ferrandi
Chiara
C
Perrin
Dominique
D
Rommel
Christian
C
Hooft van Huijsduijnen
Rob
R
D000818:Animals; D002633:Chemotaxis / Q000187:drug effects*; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D009000:Monocytes / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000009:adverse effects / Q000737:chemistry*; D015398:Signal Transduction; D013864:Thioglycolates / Q000494:pharmacology
D013864:Thioglycolates; D010744:Phosphoric Monoester Hydrolases; C516888:PTPRO protein, human; D017027:Protein Tyrosine Phosphatases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3