STAT4 is largely activated by IL-12. Consistently, Stat4 deficient mice displayed impaired TH1 differentiation (Kaplan et al., 1996; Thierfelder et al., 1996), decreased nature killer (NK) cell cytotoxicity, and abrogated IFN-y production upon IL-12 treatment. These data support a physiological role of STAT4 in IL-12 signaling.


STAT5A and STAT5B are encoded by two different genes but they share over 90% sequence homology (Ihle, 2001b). STAT5A and STAT5B are activated by a variety of cytokines, including growth hormone (GH), prolactin (PRL), and IL-2 (Ihle, 2001a). Gene targeting studies suggest that STAT5A and STAT5B have both redundant and non-redundant roles in cytokine signaling. StatSa deficient mice showed defects in mammary gland development and lactation, consistent with the essential role of STAT5A in PRL signaling (Liu et al., 1997). Stat5b null mice were defective in growth hormone (GH)-mediated sexual dimorphic growth, suggesting an important role of STAT5B in GH signaling (Udy et al., 1997). Although Stat5a or Stat5b null mice showed defects in IL-2-mediated T cell proliferation and NK cell functions (Imada et al., 1998; Nakajima et al., 1997), Stat5a/5b double knockout mice displayed even more severe phenotypes. Stat5a/5b double knockout mice had no NK cells and T cells from these mice were defective in anti-CD3-mediated cell proliferation (Teglund et al., 1998).


Biochemical studies indicate that STAT6 is mainly activated by IL-4 and IL-13. Consistently, Stat6 null mice showed defective TH2 responses and enhanced TH1 differentiation (Shimoda et al., 1996; Takcda et al.. 1996). Furthermore, the IL-4/IL-13-mediated expulsion of the gastrointestingal parasite was defective in Stat6 null mice (Urban et al., 1998). These results support a critical role of STAT6 in IL-4/IL-13 signaling.


The STAT signaling pathway plays an important role in the control of many fundamental biological processes. Great progress has been made in the understanding of the molecular basis of STAT-mediated gene regulation. Since abnormal STAT signaling is associated with immune disorders and cancers, one of the great challenges in the STAT field is to understand the regulation of STAT signaling under both physiological and pathological conditions. These studies will lead to the design of rationale therapeutic strategies for the treatment of human diseases.


Supported by grants from The National Institutes of Health (K.S.).

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