2008 PBL Cat_mech_r.qxd:PBL Catalog.mech 11/29/07 1:50 PM Page 8
Application Note
Stat2 dependent regulation of MHC class II expression (continued)
To determine how Stat2 negatively regulates the IFN-α dependent from Interferons to Cytokines J. Biol. Chem. In press.
Stat1 activation, additional studies were carried out. Tissue culture 4. Zhao, W., E. N. Cha, C. Lee, C. Y. Park, and C. Schindler (2007). Stat2-
media washout studies revealed prolonged Stat1 activation was Dependent Regulation of MHC Class II Expression. J. Immunol.
dependent on the continuous presence of IFN-α. A subsequent study 179:463-471.
evaluating aged IFN-α confirmed it retains its full biological activity for 5. Park, C., S. Li, E. Cha, and C. Schindler (2000). Immune response in
at least 24 h at 37 °C (not shown). Thus, the requirement of continuous Stat2 knockout mice. Immunity 13:795-804.
IFN-α for prolonged Stat1 activation phenotype, suggested that Stat2 6. Fenner, J. E., R. Starr, A. L. Cornish, J. G. Zhang, D. Metcalf, R. D.
(i.e., ISGF-3) normally directs the expression of a negative regulator. Schreiber, K. Sheehan, D. J. Hilton, W. S. Alexander, and P. J. Hertzog
Subsequent studies revealed that one candidate regulator, Socs-1 (4, (2006). Suppressor of cytokine signaling 1 regulates the immune
6), is induced in a Stat2-ISGF-3 dependent manner. Specifically, IFN-α response to infection by a unique inhibition of type I interferon
potently induced Socs-1 expression in wild type, but not Stat2-/- activity. Nat. Immunol. 7:33-39.
macrophages (Fig. 2C). In contrast, the even stronger IFN-γ dependent 7. Meraz, M. A., J. M. White, K. C. Sheehan, E. A. Bach, S. J. Rodig, A. S.
stimulation of Socs-1 was Stat2 independent. These studies identify Dighe, D. H. Kaplan, J. K. Riley, A. C. Greenlund, D. Campbell, K.
Socs-1 as an important IFN-α target gene. Carver-Moore, R. N. DuBois, R. Clark, M. Aguet, and R. D. Schreiber
(1996). Targeted disruption of the Stat1 gene in mice reveals
Discussion unexpected physiological specificity in the JAK-STAT pathway. Cell
Type I and Type II IFNs play important and distinct roles in regulating 84:431-442.
immune response. These biochemical and genetic studies suggest that 8. Park, C., and C. Schindler (1998). Protein-DNA interactions in
the IFN-αdependent induction of Socs-1 expression plays a critical role Interferon-γ signaling. Methods: Comp. Methods in Enzymol.
in regulating the kinetics of Stat1 activation. Subsequent studies with 15:175-188.
ectopic Socs-1 expression confirm that this important negative 9. Schindler, C., K. Shuai, V. Prezioso, and J. E. Darnell. (1992).
regulator plays a critical role in distinguishing the nature of the Interferon-dependent tyrosine phosphorylation of a latent
biological response between type I and type II IFNs in macrophages (4). cytoplasmic transcription factor. Science 257:809-813.
10. Improta, T., C. Schindler, C. M. Horvath, I. M. Kerr, G. R. Stark, and J. E.
References Darnell, Jr. (1994). Transcription factor ISGF-3 formation requires
1. Pestka, S., C. D. Krause, and M. R. Walter (2004). Interferons, phosphorylated Stat91 protein, but Stat113 protein is
interferon-like cytokines, and their receptors. Immunol. Rev. 202:8- phosphorylated independently of Stat91 protein. Proc. Natl. Acad.
32. Sci. U S A 91:4776-4780.
2. Rosenzweig, S. D., and S. M. Holland (2005). Defects in the 11. Song, L., S. Bhattacharya, A. A. Yunus, C. D. Lima, and C. Schindler.
interferon-gamma and interleukin-12 pathways. Immunol Rev (2006). Stat1 and SUMO modification. Blood 108:3237-3244.
203:38-47.
3. Schindler, C., D. E. Levy, and T. Decker (2007). JAK-STAT Signaling:
PBLInterferonSource Toll Free: 1 877- PBL-8881
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