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 (gp130(F759/F759)) were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction. In contrast, the STAT3 signal-deficient mice (gp130(FXXQ/FXXQ)) died perinatally, like the gp130-deficient mice (gp130(D/D)). The gp13(F759/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 gp13(F759/F759) mice, while they were decreased in the gp130(FXXQ/FXXQ) immune system. These results indicate that the balance of positive and negative signals generated through gp130 regulates the immune responses.
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