| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Mediates TNF-
-Induced STAT1 Phosphorylation and Induction of Retinoic Acid-Inducible Gene-I in Human Cervical Cancer Cells1Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112
Retinoic acid inducible gene-I (RIG-I) plays important roles during innate immune responses to viral infections and as a transducer of cytokine signaling. The mechanisms of RIG-I up-regulation after cytokine stimulation are incompletely characterized. It was previously reported that IFN–
induces the expression of RIG-I in endothelial cells. In this study, we characterized the mechanism of type I IFN-mediated up-regulation of RIG-I in HeLa cells and found that, in addition to type I IFN, TNF-
, a cytokine that regulates innate immune responses, induced expression of RIG-I. To investigate whether TNF-- and type I IFN-mediated up-regulations of RIG-I were causally related, we studied the kinetics of these responses. Our results were consistent with a model in which TNF- functioned upstream of type I IFNs. The ability of TNF- to up-regulate RIG-I required protein synthesis, expression of functional type I IFNRs, and STAT1 signaling. We also found that IFN-
was the only IFN isoform expressed constitutively in HeLa cells and that its expression was up-regulated in response to stimulation with TNF-. The mechanism of up-regulation involved stabilization of IFN- mRNA in the absence of transcriptional activation. Silencing the expression of IFN- attenuated STAT1 expression and phosphorylation and inhibited RIG-I expression, providing additional support for the participation of IFN- upstream of STAT1. Our findings support a sequential mechanism whereby TNF- leads to stabilization of IFN- mRNA, increased IFN- synthesis, engagement of type I IFNRs, increased STAT1 expression and phosphorylation, and up-regulation of RIG-I expression. These findings have implications for our understanding of the immune responses that follow cytokine stimulation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Huntsman Cancer Foundation and by a grant from the National Institutes of Health (P01-CA73992).
2 Address correspondence and reprint requests to Dr. Diana M. Stafforini, Huntsman Cancer Institute, 2000 Circle of Hope, Suite 3364, University of Utah, Salt Lake City, UT 84112-5550. E-mail address: diana.stafforini{at}hci.utah.edu
3 Abbreviations used in this paper: RIG-I, retinoic acid-inducible gene-I; CHX, cycloheximide; poly(I:C), polyinosinic:polycytidylic acid; RNAi, RNA interference; siRNA, small interfering RNA.
This article has been cited by other articles:
|
|
 |
|
  T. Matsumiya, T. Imaizumi, H. Yoshida, K. Satoh, M. K. Topham, and D. M. Stafforini The Levels of Retinoic Acid-Inducible Gene I Are Regulated by Heat Shock Protein 90-{alpha} J. Immunol., March 1, 2009; 182(5): 2717 - 2725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Warfel and F. D'Agnillo Anthrax Lethal Toxin Enhances TNF-Induced Endothelial VCAM-1 Expression via an IFN Regulatory Factor-1-Dependent Mechanism J. Immunol., June 1, 2008; 180(11): 7516 - 7524. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
