Document Detail

Intracellular murine IFN-gamma mediates virus resistance, expression of oligoadenylate synthetase, and activation of STAT transcription factors.
MedLine Citation:
PMID:  8906836     Owner:  NLM     Status:  MEDLINE    
IFN-gamma is a pleiotropic cytokine that plays a major role in anti-infectious immune responses. The physiologic effects of IFN-gamma are thought to be mediated by the binding of extracellular IFN-gamma to its receptor at the cell surface, thereby triggering an intracellular signaling cascade. In this work, we present evidence for a completely intracellular mechanism for IFN-gamma to induce virus protection. Murine fibroblasts were transfected with the cDNA for murine IFN-gamma, and although no detectable amounts of IFN-gamma were released, these cells were resistant to lysis by the cytolytic vesicular stomatitis virus. In contrast to exogenously added IFN-gamma, the effect of the endogenously produced IFN-gamma was not abolished by treatment with neutralizing Abs. To test whether intracellular signal transduction occurs, an IFN-gamma variant was constructed with the carboxyl-terminal endoplasmic reticulum retention signal Lys-Asp-Glu-Leu (KDEL). Transfection of fibroblasts with this mutant IFN-gamma, anchored in the endoplasmic reticulum, led to virus resistance, thus demonstrating that biologic effects of this protein do not necessarily require binding to the receptor at the cell surface. However, the antiviral state induced by transfection with IFN-gamma-KDEL was strictly dependent on the presence of the IFN-gammaR, since fibroblasts derived from IFN-gammaR-deficient mice (IFN-gammaR -/-) were not rendered virus resistant. The virus resistance induced was accompanied by enhanced expression of 2'-5' oligoadenylate synthetase and constitutive activation of STAT1 (signal transducers and activators of transcription). Hence, autocrinous effects of IFN-gamma in cells naturally producing this cytokine might occur even in the absence of its secretion. The mechanisms involved in signaling appear to be identical with or closely related to those occurring after binding of IFN-gamma to its receptor at the cell surface.
A Will; U Hemmann; F Horn; M Röllinghoff; A Gessner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  157     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  1996 Nov 
Date Detail:
Created Date:  1996-12-31     Completed Date:  1996-12-31     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4576-83     Citation Subset:  AIM; IM    
Institute of Clinical Microbiology and Immunology, University of Erlangen-Nürnberg, Germany.
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MeSH Terms
2',5'-Oligoadenylate Synthetase / biosynthesis*
DNA-Binding Proteins / biosynthesis*
Endoplasmic Reticulum / chemistry,  immunology,  virology
Immunity, Innate / drug effects
Interferon-gamma / analysis*,  pharmacology*
Intracellular Fluid / immunology
L Cells (Cell Line)
Rhabdoviridae Infections / immunology*
STAT1 Transcription Factor
STAT3 Transcription Factor
Trans-Activators / biosynthesis*
Transcription Factors / biosynthesis*
Vesicular stomatitis Indiana virus / immunology*
Reg. No./Substance:
0/DNA-Binding Proteins; 0/STAT1 Transcription Factor; 0/STAT3 Transcription Factor; 0/Stat1 protein, mouse; 0/Stat3 protein, mouse; 0/Trans-Activators; 0/Transcription Factors; 82115-62-6/Interferon-gamma; EC 2.7.7.-/2',5'-Oligoadenylate Synthetase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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