• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Oct 17, 1994; 13(20): 4798–4806.
PMCID: PMC395418

Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes.

Abstract

The transcription factor interferon regulatory factor 1 (IRF-1) binds tightly to the interferon (IFN)-beta promoter and has been implicated in the induction of type I IFNs. We generated mice devoid of functional IRF-1 by targeted gene disruption. As reported by others, IRF-1-deficient mice showed a discrete phenotype: the CD4/CD8 ratio was increased and IFN-gamma-induced levels of macrophage iNO synthase mRNA were strongly diminished. However, type I IFN induction in vivo by virus or double-stranded RNA was unimpaired, as evidenced by serum IFN titers and IFN mRNA levels in spleen, liver and lung. There was also no impairment in the response of type I IFN-inducible genes. Therefore, IRF-1 is not essential for these processes in vivo.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Capecchi MR. The new mouse genetics: altering the genome by gene targeting. Trends Genet. 1989 Mar;5(3):70–76. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Clark L, Hay RT. Sequence requirement for specific interaction of an enhancer binding protein (EBP1) with DNA. Nucleic Acids Res. 1989 Jan 25;17(2):499–516. [PMC free article] [PubMed]
  • Dinter H, Hauser H. Superinduction of the human interferon-beta promoter. EMBO J. 1987 Mar;6(3):599–604. [PMC free article] [PubMed]
  • Doetschman T, Gregg RG, Maeda N, Hooper ML, Melton DW, Thompson S, Smithies O. Targetted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature. 1987 Dec 10;330(6148):576–578. [PubMed]
  • Dron M, Lacasa M, Tovey MG. Priming affects the activity of a specific region of the promoter of the human beta interferon gene. Mol Cell Biol. 1990 Feb;10(2):854–858. [PMC free article] [PubMed]
  • Du W, Maniatis T. An ATF/CREB binding site is required for virus induction of the human interferon beta gene [corrected]. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2150–2154. [PMC free article] [PubMed]
  • Du W, Thanos D, Maniatis T. Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. Cell. 1993 Sep 10;74(5):887–898. [PubMed]
  • Enoch T, Zinn K, Maniatis T. Activation of the human beta-interferon gene requires an interferon-inducible factor. Mol Cell Biol. 1986 Mar;6(3):801–810. [PMC free article] [PubMed]
  • Flenniken AM, Galabru J, Rutherford MN, Hovanessian AG, Williams BR. Expression of interferon-induced genes in different tissues of mice. J Virol. 1988 Sep;62(9):3077–3083. [PMC free article] [PubMed]
  • Fujita T, Sakakibara J, Sudo Y, Miyamoto M, Kimura Y, Taniguchi T. Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements. EMBO J. 1988 Nov;7(11):3397–3405. [PMC free article] [PubMed]
  • Fujita T, Kimura Y, Miyamoto M, Barsoumian EL, Taniguchi T. Induction of endogenous IFN-alpha and IFN-beta genes by a regulatory transcription factor, IRF-1. Nature. 1989 Jan 19;337(6204):270–272. [PubMed]
  • Fujita T, Miyamoto M, Kimura Y, Hammer J, Taniguchi T. Involvement of a cis-element that binds an H2TF-1/NF kappa B like factor(s) in the virus-induced interferon-beta gene expression. Nucleic Acids Res. 1989 May 11;17(9):3335–3346. [PMC free article] [PubMed]
  • Harada H, Fujita T, Miyamoto M, Kimura Y, Maruyama M, Furia A, Miyata T, Taniguchi T. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell. 1989 Aug 25;58(4):729–739. [PubMed]
  • Harada H, Willison K, Sakakibara J, Miyamoto M, Fujita T, Taniguchi T. Absence of the type I IFN system in EC cells: transcriptional activator (IRF-1) and repressor (IRF-2) genes are developmentally regulated. Cell. 1990 Oct 19;63(2):303–312. [PubMed]
  • Heard JM, Herbomel P, Ott MO, Mottura-Rollier A, Weiss M, Yaniv M. Determinants of rat albumin promoter tissue specificity analyzed by an improved transient expression system. Mol Cell Biol. 1987 Jul;7(7):2425–2434. [PMC free article] [PubMed]
  • Hiscott J, Alper D, Cohen L, Leblanc JF, Sportza L, Wong A, Xanthoudakis S. Induction of human interferon gene expression is associated with a nuclear factor that interacts with the NF-kappa B site of the human immunodeficiency virus enhancer. J Virol. 1989 Jun;63(6):2557–2566. [PMC free article] [PubMed]
  • Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M. Immune response in mice that lack the interferon-gamma receptor. Science. 1993 Mar 19;259(5102):1742–1745. [PubMed]
  • Hunter T. Signal transduction. Cytokine connections. Nature. 1993 Nov 11;366(6451):114–116. [PubMed]
  • Kamijo R, Harada H, Matsuyama T, Bosland M, Gerecitano J, Shapiro D, Le J, Koh SI, Kimura T, Green SJ, et al. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science. 1994 Mar 18;263(5153):1612–1615. [PubMed]
  • Kelley KA, Pitha PM. Differential effect of poly rI.rC and Newcastle disease virus on the expression of interferon and cellular genes in mouse cells. Virology. 1985 Dec;147(2):382–393. [PubMed]
  • Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 1991 Aug 11;19(15):4293–4293. [PMC free article] [PubMed]
  • Lenardo MJ, Fan CM, Maniatis T, Baltimore D. The involvement of NF-kappa B in beta-interferon gene regulation reveals its role as widely inducible mediator of signal transduction. Cell. 1989 Apr 21;57(2):287–294. [PubMed]
  • Matsuyama T, Kimura T, Kitagawa M, Pfeffer K, Kawakami T, Watanabe N, Kündig TM, Amakawa R, Kishihara K, Wakeham A, et al. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell. 1993 Oct 8;75(1):83–97. [PubMed]
  • McMahon AP, Bradley A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 1990 Sep 21;62(6):1073–1085. [PubMed]
  • Miyamoto M, Fujita T, Kimura Y, Maruyama M, Harada H, Sudo Y, Miyata T, Taniguchi T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell. 1988 Sep 9;54(6):903–913. [PubMed]
  • Müller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994 Jun 24;264(5167):1918–1921. [PubMed]
  • Näf D, Hardin SE, Weissmann C. Multimerization of AAGTGA and GAAAGT generates sequences that mediate virus inducibility by mimicking an interferon promoter element. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1369–1373. [PMC free article] [PubMed]
  • Pellegrini S, Schindler C. Early events in signalling by interferons. Trends Biochem Sci. 1993 Sep;18(9):338–342. [PubMed]
  • Pine R, Decker T, Kessler DS, Levy DE, Darnell JE., Jr Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Mol Cell Biol. 1990 Jun;10(6):2448–2457. [PMC free article] [PubMed]
  • Raj NB, Pitha PM. Analysis of interferon mRNA in human fibroblast cells induced to produce interferon. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7426–7430. [PMC free article] [PubMed]
  • Reis LF, Harada H, Wolchok JD, Taniguchi T, Vilcek J. Critical role of a common transcription factor, IRF-1, in the regulation of IFN-beta and IFN-inducible genes. EMBO J. 1992 Jan;11(1):185–193. [PMC free article] [PubMed]
  • Ruffner H, Reis LF, Näf D, Weissmann C. Induction of type I interferon genes and interferon-inducible genes in embryonal stem cells devoid of interferon regulatory factor 1. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11503–11507. [PMC free article] [PubMed]
  • Sehgal PB, Dobberstein B, Tamm I. Interferon messenger RNA content of human fibroblasts during induction, shutoff, and superinduction of interferon production. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3409–3413. [PMC free article] [PubMed]
  • Stewart WE, 2nd, Gosser LB, Lockart RZ., Jr Priming: a nonantiviral function of interferon. J Virol. 1971 Jun;7(6):792–801. [PMC free article] [PubMed]
  • Tan YH, Armstrong JA, Ke YH, Ho M. Regulation of cellular interferon production: enhancement by antimetabolites. Proc Natl Acad Sci U S A. 1970 Sep;67(1):464–471. [PMC free article] [PubMed]
  • Thanos D, Maniatis T. The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell. 1992 Nov 27;71(5):777–789. [PubMed]
  • Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987 Nov 6;51(3):503–512. [PubMed]
  • Veals SA, Schindler C, Leonard D, Fu XY, Aebersold R, Darnell JE, Jr, Levy DE. Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol Cell Biol. 1992 Aug;12(8):3315–3324. [PMC free article] [PubMed]
  • Vilcek J, Havell EA. Stabilization of interferon messenger RNA activity by treatment of cells with metabolic inhibitors and lowering of the incubation temperature. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3909–3913. [PMC free article] [PubMed]
  • Visvanathan KV, Goodbourn S. Double-stranded RNA activates binding of NF-kappa B to an inducible element in the human beta-interferon promoter. EMBO J. 1989 Apr;8(4):1129–1138. [PMC free article] [PubMed]
  • Weber H, Valenzuela D, Lujber G, Gubler M, Weissmann C. Single amino acid changes that render human IFN-alpha 2 biologically active on mouse cells. EMBO J. 1987 Mar;6(3):591–598. [PMC free article] [PubMed]
  • Whiteside ST, Visvanathan KV, Goodbourn S. Identification of novel factors that bind to the PRD I region of the human beta-interferon promoter. Nucleic Acids Res. 1992 Apr 11;20(7):1531–1538. [PMC free article] [PubMed]
  • Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992 Apr 10;256(5054):225–228. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...