miércoles, 11 de abril de 2012

The Tumor Suppressor ARF Regulates Innate Immune Responses in Mice

The Tumor Suppressor ARF Regulates Innate Immune Responses in Mice

The Tumor Suppressor ARF Regulates Innate Immune Responses in Mice

  1. Sonsoles Hortelano§
+ Author Affiliations
  1. *Instituto de Investigaciones Biomédicas Alberto Sols (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), 28029 Madrid, Spain;
  2. Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain;
  3. Oncohematología y Trasplante, Fundación de Investigación Biomédica, Hospital Universitario Niño Jesús and Instituto de Investigación Sanitaria Hospital La Princesa, 28009 Madrid, Spain; and
  4. §Unidad de Inflamación y Cáncer, Área de Biología Celular y Desarrollo, Centro Nacional de Microbiología-Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain
  1. Address correspondence and reprint requests to Dr. Sonsoles Hortelano, Unidad de Inflamación y Cáncer, Área de Biología Celular y del Desarrollo, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda-Pozuelo, kilometre 2,200, 28220 Majadahonda, Madrid, Spain. E-mail address: shortelano@isciii.es
  1. 1 P.G.T. and R.L.-F. contributed equally to this work.


The innate immune system is the first line of defense against invading organisms, and TLRs are the main sensors of microbial components, initiating signaling pathways that induce the production of proinflammatory cytokines and type I IFNs. An antiviral action for the tumor suppressor alternative reading frame (ARF) has been reported; however, the precise role of ARF in innate immunity is unknown. In this study, we show that ARF plays an important role in regulation of inflammatory responses. In peritoneal macrophages and bone marrow-derived macrophages from ARF-deficient animals, the induction of proinflammatory cytokines and chemokines by TLR ligands was severely impaired. The altered responses of ARF−/− cells to TLR ligands result from aberrant activation of intracellular signaling molecules including MAPKs, IκBα degradation, and NF-κB activation. Additionally, animals lacking ARF were resistant to LPS-induced endotoxic shock. This impaired activation of inflammation in ARF−/− mice was not restricted to TLRs, as it was also shown in response to non-TLR signaling pathways. Thus, ARF−/− mice were also unable to trigger a proper inflammatory response in experimental peritonitis or in 12-O-tetradecanoylphorbol-13-acetate–induced edema. Overexpression of ARF, but not its downstream target p53, rescued the ARF-deficient phenotype, increasing TLR4 levels and restoring inflammatory reaction. An increase in the E2F1 protein levels observed in ARF−/− macrophages at basal condition and after LPS stimulation may be involved in the impaired response in this system, as E2F1 has been described as an inflammatory suppressor. These results indicate that tumor suppressor ARF is a new regulator of inflammatory cell signaling.


  • This work was supported by Grant PI08.0070 from the Fondo de Investigaciones Sanitarias, MPY 1410/09 from Instituto de Salud Carlos III, and a Fundación Mutua Madrileña award (to S.H.). P.G.T. was supported by a Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares grant. A.L. was supported by Ramón y Cajal Fellowship RYC-2004-000367. Centro Nacional de Investigaciones Cardiovasculares is supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation.
  • The microarray data presented in this article have been submitted to the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE32446) under accession number GSE32446.
  • The online version of this article contains supplemental material.
  • Abbreviations used in this article:
    alternative reading frame
    bone marrow-derived macrophage
    lipoteichoic acid
    polyinosinic-polycytidylic acid
    polypyrimidine tract-binding protein-associated splicing factor
    12-O-tetradecanoylphorbol acetate
    TIR domain-containing adapter inducing IFN-β
    wild type.

  • Received December 15, 2010.
  • Accepted October 15, 2011.

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