title: T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease.
abstract: 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.
authors.affiliation: Division of Experimental Medicine, McGill University, Montreal, QC, Canada. wayne.lapp@mcgill.ca
authors.forename: Krista M
authors.initials: KM
authors.lastname: Heinonen
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Nestel
authors.forename: Evan W
authors.initials: EW
authors.lastname: Newell
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Charette
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Seemayer
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Wayne S
authors.initials: WS
authors.lastname: Lapp
mesh_terms: 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
chemical_list: 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