Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses

T Ohtani; K Ishihara; T Atsumi; K Nishida; Y Kaneko; T Miyata; S Itoh; M Narimatsu; H Maeda; T Fukada; M Itoh; H Okano; M Hibi; T Hirano

doi:10.1016/s1074-7613(00)80162-4

Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses

Immunity. 2000 Jan;12(1):95-105. doi: 10.1016/s1074-7613(00)80162-4.

Authors

T Ohtani¹, K Ishihara, T Atsumi, K Nishida, Y Kaneko, T Miyata, S Itoh, M Narimatsu, H Maeda, T Fukada, M Itoh, H Okano, M Hibi, T Hirano

Affiliation

¹ Division of Molecular Oncology (C7), Biomedical Research Center, Osaka University Graduate School of Medicine, Japan.

PMID: 10661409
DOI: 10.1016/s1074-7613(00)80162-4

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute-Phase Reaction
Animals
Antigens, CD / genetics
Antigens, CD / immunology*
Astrocytes / cytology
Astrocytes / immunology
B-Lymphocytes / immunology
CD40 Antigens / immunology
Cell Differentiation
Cells, Cultured
Cytokine Receptor gp130
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology*
Embryonic and Fetal Development
Hematopoiesis / genetics
Hemocyanins / immunology
Humans
Immunoglobulin G / immunology
Interferon-gamma / biosynthesis
Interleukin-4 / biosynthesis
Intracellular Signaling Peptides and Proteins
Lymphatic Diseases / immunology
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology*
Mice
Mice, Knockout
Mice, Transgenic
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases / genetics
Protein Tyrosine Phosphatases / immunology*
STAT3 Transcription Factor
Signal Transduction / immunology*
Splenomegaly / immunology
Trans-Activators / genetics
Trans-Activators / immunology*

Substances

2,4-dinitrophenyl keyhole limpet hemocyanin
Antigens, CD
CD40 Antigens
DNA-Binding Proteins
IL6ST protein, human
Il6st protein, mouse
Immunoglobulin G
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins
STAT3 Transcription Factor
STAT3 protein, human
Stat3 protein, mouse
Trans-Activators
Cytokine Receptor gp130
Interleukin-4
Interferon-gamma
Hemocyanins
PTPN11 protein, human
PTPN6 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases
Ptpn11 protein, mouse
Ptpn6 protein, mouse