TY - JOUR
T1 - GLEPP1/Protein-tyrosine Phosphatase ϕ Inhibitors Block Chemotaxis in Vitro and in Vivo and Improve Murine Ulcerative Colitis
AU - Gobert, R.P.
AU - Van Den Eijinden, M.
AU - Szyndralewiez, C.
AU - Jorand-Lebrun, C.
AU - Swinnen, D.
AU - Chen, L.
AU - Gillieron, C.
AU - Pixley, Fiona
AU - Juillard, P.
AU - Gerber, G.
AU - Johnson-Leger, C.
AU - Halazy, S.
AU - Camps, M.
AU - Bombrun, A.
AU - Shipp, M.
AU - Vitte, P.A.
AU - Ardissone, V.
AU - Ferrandi, C.
AU - Perrin, D.
AU - Rommel, C.
AU - Hooft Van Huijsduijnen, R.
PY - 2009
Y1 - 2009
N2 - We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase ϕ. 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.
AB - We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase ϕ. 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.
U2 - 10.1074/jbc.M807241200
DO - 10.1074/jbc.M807241200
M3 - Article
C2 - 19233845
SN - 0021-9258
VL - 284
SP - 11385
EP - 11395
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 17
ER -