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Interleukin-6-induced proliferation of pre-B cells mediated by receptor complexes lacking the SHP2/SOCS3 recruitment sites revisited.

Interleukin-6 (IL-6) induces B-cell proliferation by binding to receptor complexes composed of a specific alpha-receptor (gp80; CD126) and the signal transducing receptor subunit gp130 (CD130). Immediately after receptor complex activation, signal transducers and activators of transcription (STATs) 1 and 3 and the Src-homology domain-containing protein tyrosine phosphatase 2 (SHP2) are recruited to gp130 and subsequently tyrosine phosphorylated. The activated dimerized STATs translocate to the nucleus and bind to enhancer elements of IL-6-inducible genes. SHP2 acts as an adapter and links the Jak/STAT pathway to the Ras/Raf/MAPK cascade but it is also involved in signal attenuation. Whereas STAT3 activation appears to be crucial for all biological activities of IL-6, the requirement of SHP2-activation depends on the individual biological response analyzed. The requirement of SHP2 activation for the pre-B cell (Ba/F3) proliferation has been reported previously [Fukada, T., Hibi, M., Yamanaka, Y., Takahashi-Tezuka, M., Fujitani, Y., Yamaguchi, T., Nakajima, K. & Hirano, T. (1996) Immunity 5, 449-460]. In contrast, we have recently demonstrated that the presence of a single STAT-recruitment site within gp130 is sufficient for IL-6- induced proliferation of Ba/F3 cells [Schmitz, J., Dahmen, H., Grimm, C., Gendo, C., Müller-Newen, G., Heinrich, P.C. & Schaper, F. (2000) J. Immunol. 164, 848-854]. To unravel this discrepancy we analyzed the IL-6-induced dose-dependent proliferation of Ba/F3 cells mediated by receptor complexes lacking SHP2/SOCS3 recruitment sites. Surprisingly, pre-B cells, after stimulation with low amounts of IL-6, proliferate much more efficiently in the absence of the activated SHP2 than in the presence of the tyrosine phosphatase. Therefore, SHP2 activation appears to be relevant for IL-6-induced proliferation only after stimulation with very large amounts of IL-6.