Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses.
We generated a series of knockin mouse lines, in which the cytokine receptor gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse gp130 gene with human gp130 mutant cDNAs. The SHP2 signal-deficient mice (gp130F759/F759 were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction. In contrast, the STAT3 signal-deficient mice (gp130FXQ/FXXQ) died perinatally, like the gp130-deficient mice (gp130D/D). The gp130F759/F759 mice showed prolonged gp130-induced STAT3 activation, indicating a negative regulatory role for SHP2. Th1-type cytokine production and IgG2a and IgG2b production were increased in the gp130F759/F759 mice, while they were decreased in the gp130FXXQ/FXXQ immune system. These results indicate that the balance of positive and negative signals generated through gp130 regulates the immune responses.
Ohtani
T
T
Division of Molecular Oncology (C7), Biomedical Research Center, Osaka University Graduate School of Medicine, Japan.
Ishihara
K
K
Atsumi
T
T
Nishida
K
K
Kaneko
Y
Y
Miyata
T
T
Itoh
S
S
Narimatsu
M
M
Maeda
H
H
Fukada
T
T
Itoh
M
M
Okano
H
H
Hibi
M
M
Hirano
T
T
D000210:Acute-Phase Reaction; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001253:Astrocytes / Q000166:cytology / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005314:Embryonic and Fetal Development; D006410:Hematopoiesis / Q000235:genetics; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D008206:Lymphatic Diseases / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D013163:Splenomegaly / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*
C042158:2,4-dinitrophenyl keyhole limpet hemocyanin; D015703:Antigens, CD; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D015847:Interleukin-4; D007371:Interferon-gamma; D006433:Hemocyanins; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse