Pleiotropic functions of cytokines and STAT5

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We have been working on molecular mechanisms of the pleiotropic functions of cytokines using the constitutively active mutants of STAT5 (Onishi et al. Mol Cell Biol, 1998; Ariyoshi et al. J Biol Chem, 2000) which we identified by PCR-driven random mutagenesis followed by retrovirus-mediated expression screening. STAT5 is a transcription factor known to induce the expression of a variety of target genes. We previously demonstrated that STAT5 could induce proliferation, differentiation, and apoptosis in the same cells through induction of pim-1, p21 and SOCS1, respectively (Nosaka et al, EMBO J, 1999). We have now identified a novel mechanism by which the constitutively active STAT5 induced macrophage differentiation of M1 cells ; the active STAT5 induced macrophage differentiation via autocrine production of IL-6 (Kawashima et al. J Immunol, 2001). Interestingly, the promoter of the IL-6 gene does not contain the biding site of STAT5, and the induction of IL-6 by the active STAT5 was mediated through activation of NFkB. Now we are investigating the underlying molecular mechanism, and the preliminary results indicate that a secreted protein induced by STAT5 activation is responsible for IL-6 production (Nakamura et al. J Biol Chem, 2002). The identification of this secreted protein is now ongoing.