HSV-1-Induced SOCS-1 Expression in Keratinocytes: Use of a SOCS-1 Antagonist to Block a Novel Mechanism of Viral Immune Evasion

Kenneth G. Frey, Chulbul M.I. Ahmed, Rea Dabelic, Lindsey D. Jager, Ezra N. Noon-Song, S. Mohammad Haider, Howard M. Johnson, Nancy J. Bigley

Research output: Contribution to journalArticlepeer-review

Abstract

Keratinocytes are important for the acute phase of HSV-1 infection and subsequent persistence in sensory nervous tissue. In this study, we showed that keratinocytes (HEL-30) were refractory to IFN-γ induction of an antiviral state to HSV-1 infection, while IFN-γ did induce an antiviral state in fibroblasts (L929). This led us to examine the possible role of suppressor of cytokine signaling-1 (SOCS-1) in this refractiveness. RT-PCR analysis of SOCS-1 mRNA expression in HSV-1-infected cells showed a 4-fold increase for keratinocytes while having a negligible effect on fibroblasts. A similar pattern was observed at the level of SOCS-1 protein induction. Activation of STAT1α in keratinocytes was inhibited by HSV-1 infection. A direct effect of HSV-1 on the SOCS-1 promoter was shown in a luciferase reporter gene assay. We have developed a small peptide antagonist of SOCS-1, pJAK2(1001–1013), that had both an antiviral effect in keratinocytes against HSV-1 as well as a synergistic effect on IFN-γ induction of an antiviral state. HSV-1 ICP0 mutant was inhibited by IFN-γ in HEL-30 cells and was less effective than wild-type virus in induction of SOCS-1 promoter. We conclude that SOCS-1 plays an important role in the inhibition of the antiviral effect of IFN-γ in keratinocytes infected with HSV-1. The use of SOCS-1 antagonist to abrogate this refractiveness could have a transformational effect on therapy against viral infections.

Original languageEnglish
Pages (from-to)1253-1262
Number of pages10
JournalJournal of Immunology
Volume183
Issue number2
DOIs
StatePublished - Jul 15 2009

ASJC Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

Keywords

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Cell Line, Tumor
  • Herpesvirus 1, Human / immunology*
  • Herpesvirus 1, Human / pathogenicity
  • Humans
  • Immunity
  • Interferon-Stiumlated Gene Factor 3 / antagonists & inhibitors
  • Interferon-gamma / immunology
  • Keratinocytes / metabolism
  • Keratinocytes / virology*
  • Peptides / pharmacology
  • Promotor Regions, Genetic
  • RNA, Messenger / analysis
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / antagonists & inhibitors
  • Suppressor of Cytokine Signaling Proteins / genetics*
  • Inferon-Stimulated Gene Factor 3
  • Peptides
  • RNA, Messenger
  • SOCS1 protein, human
  • gamma interferon activation factor
  • Interferon-gamma

Disciplines

  • Medical Cell Biology
  • Medical Neurobiology
  • Medical Physiology
  • Neurosciences
  • Physiological Processes

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