T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease.
The deregulation of the immune response is a critical component in inflammatory disease. Recent in vitro data show that T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of cytokine signaling. Furthermore, tc-ptp(-/-) mice display immune defects and die within 5 weeks of birth. We report here that tc-ptp(-/-) mice develop progressive systemic inflammatory disease as shown by chronic myocarditis, gastritis, nephritis, and sialadenitis as well as elevated serum interferon-gamma. The widespread mononuclear cellular infiltrates correlate with exaggerated interferon-gamma, tumor necrosis factor-alpha, interleukin-12, and nitric oxide production in vivo. Macrophages grown from tc-ptp(-/-) mice are inherently hypersensitive to lipopolysaccharide, which can also be detected in vivo as an increased susceptibility to endotoxic shock. These results identify T-cell protein tyrosine phosphatase as a key modulator of inflammatory signals and macrophage function.
Heinonen
Krista M
KM
Division of Experimental Medicine, McGill University, Montreal, QC, Canada. wayne.lapp@mcgill.ca
Nestel
Frederick P
FP
Newell
Evan W
EW
Charette
Gabrielle
G
Seemayer
Thomas A
TA
Tremblay
Michel L
ML
Lapp
Wayne S
WS
D000818:Animals; D002478:Cells, Cultured; D007249:Inflammation / Q000201:enzymology*; D018836:Inflammation Mediators; D007371:Interferon-gamma / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D012772:Shock, Septic / Q000209:etiology; D013601:T-Lymphocytes / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D017027:Protein Tyrosine Phosphatases