Targeted deletion of the STAT1 gene in mice leads to compromised innate immunity

Joan Durbin, R. Harkenmiller, M. C. Simon, D. E. Levy

Research output: Contribution to journalArticle

Abstract

Cytokines and growth factors are secreted polypeptides which modulate diverse physiological functions. We have been studying interferon (IFN) signal transduction pathways that activate gene expression. IFNα activates a multimeric transcription factor, ISGF3, through tyrosine phosphorylation of STAT1 and STAT2. IFNγ induces tyrosine phosphorylation of only the STAT1 protein, resulting in assembly of a distinct transcription factor, GAF. Remarkably, STAT1 also becomes phosphorylated in response to a large number of other cytokines and growth factors including EGF, PDGF, LIF, oncostatin M, IL6, and IL10. To understand better the diverse functions of STAT1 activation we have chosen to study the consequences of a STAT1 null mutation. We have disrupted the gene for STAT1 by gene targeting in ES cells and in mice. STAT1-/animals are born at the expected frequency and are indistinguishable from wild type littermates at birth, but none has suvived past weaning outside of SPF conditions. Development of lymphocyte and macrophage populations in mutant embryos and newborns, as well as in STAT1 -/- ES cells differentiated in vitro, appeared normal. However, all mutant cells tested were completely resistant to IFN. The resulting deficiency in immune function led to early death from opportunistic infection, and exquisite sensitivity to viral infection. This work is supported by the NIH, the ACS, and the Society for Pediatric Pathology.

Original languageEnglish (US)
JournalFASEB Journal
Volume10
Issue number6
StatePublished - Dec 1 1996
Externally publishedYes

Fingerprint

Gene Deletion
Innate Immunity
Interferons
Genes
Phosphorylation
Tyrosine
Interferon-Stimulated Gene Factor 3
Intercellular Signaling Peptides and Proteins
Oncostatin M
STAT1 Transcription Factor
Cytokines
Signal transduction
Pediatrics
Gene Targeting
Lymphocytes
Macrophages
Opportunistic Infections
Pathology
Virus Diseases
Weaning

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Durbin, Joan ; Harkenmiller, R. ; Simon, M. C. ; Levy, D. E. / Targeted deletion of the STAT1 gene in mice leads to compromised innate immunity. In: FASEB Journal. 1996 ; Vol. 10, No. 6.
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Targeted deletion of the STAT1 gene in mice leads to compromised innate immunity. / Durbin, Joan; Harkenmiller, R.; Simon, M. C.; Levy, D. E.

In: FASEB Journal, Vol. 10, No. 6, 01.12.1996.

Research output: Contribution to journalArticle

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