1. ¹Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School – The University of Medicine and Dentistry of New Jersey, 675 Hoes Lane West, Piscataway, NJ 08855, USA
2. ²Department of Biochemistry & Molecular Biology, New Jersey Medical School – The University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07101, USA
3. ¹Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903-2681, USA
4. ⁴PBL Biomedical Laboratories, 131 Ethel Road West, Suite 6, Piscataway, NJ 08854-5900, USA

Correspondence: Sidney Pestka, Tel: 1-732-235-4567; Fax: 1-732-235-5223; E-mail: pestka@umdnj.edu

Abstract

The activation of Stat1 by the interferon-gamma (IFN-) receptor complex is responsible for the transcription of a significant portion of IFN- induced genes. Many of these genes are responsible for the induction of an apoptotic state in response to IFN-. In the absence of Stat1 activation, IFN- instead induces a proliferative response. Modifying Stat1 activation by IFN- may have pharmacological benefits. We report that the rate of activation of Stat1 can be altered in HeLa cells by overexpressing either the IFN-R1 chain or the IFN-R2 chain. These alterations occur in hematopoietic cell lines: Raji cells and monocytic cell lines, which have average and above-average IFN-R2 surface expression, activate Stat1 similarly to HeLa cells and HeLa cells overexpressing IFNR2, respectively. The rapid Stat1 activation seen in HeLa cells can be inhibited by overexpressing a chimeric IFN-R2 chain that does not bind Jak2 or (when high concentrations of IFN- are used) by overexpressing IFN-R1. These data are consistent with a model in which the recruitment of additional Jak2 activity to a signaling complex accelerates the rate of Stat1 activation. We conclude that the rate of activation of Stat1 in cells by IFN- can be modified by regulating either receptor chain and speculate that pharmacological agents which modify receptor chain expression may alter IFN- receptor signal transduction.