Type I Interferons Regulate Inflammatory Cell Trafficking and Macrophage Inflammatory Protein 1alpha Delivery to the Liver

J Clin Invest. 2002 Aug;110(3):321-30. doi: 10.1172/JCI15376.

Abstract

Macrophage inflammatory protein 1alpha (MIP-1alpha, CCL3) is critical for liver NK cell inflammation and delivery of IFN-gamma to mediate downstream protective responses against murine cytomegalovirus (MCMV) infections. This system was used to evaluate the upstream contribution of the type 1 IFNs, IFN-alpha/beta, in promotion of MIP-1alpha production. Mice deficient in IFN-alpha/beta functions, as a result of mutation in the receptor for these cytokines (IFN-alpha/betaR(-)), were profoundly deficient in MIP-1alpha expression and accumulation of NK cells and macrophages in the liver and had increased sensitivity to MCMV infection. The cytokines themselves were responsible for the immunoregulatory effects, since administration of recombinant IFN-alpha (rIFN-alpha) to immunocompetent mice also induced these changes. IFN-alpha/beta was required for NK cell accumulation during infection, and MIP-1alpha was required for NK cell accumulation in response to administered rIFN-alpha. In vivo trafficking assays demonstrated a requirement for IFN-alpha/betaR signaling for leukocyte localization in, and delivery of MIP-1alpha-producing macrophages to, the liver. These results extend characterization of the cytokine and chemokine cascade required for protection against viral infections in tissues by defining IFN-alpha/beta-dependent mechanisms promoting MIP-1alpha production and the resulting hepatic accumulation of NK cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport
  • Cell Movement
  • Chemokine CCL3
  • Chemokine CCL4
  • Female
  • Herpesviridae Infections / immunology
  • Humans
  • Interferon Type I / administration & dosage
  • Interferon Type I / immunology
  • Interferon-alpha / biosynthesis
  • Interferon-alpha / immunology*
  • Interferon-beta / biosynthesis
  • Interferon-beta / immunology*
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Liver / immunology*
  • Liver / pathology
  • Macrophage Inflammatory Proteins / biosynthesis
  • Macrophage Inflammatory Proteins / genetics
  • Macrophage Inflammatory Proteins / immunology*
  • Macrophages / cytology
  • Macrophages / immunology*
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / immunology
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / immunology
  • Recombinant Proteins

Substances

  • Chemokine CCL3
  • Chemokine CCL4
  • Interferon Type I
  • Interferon-alpha
  • Macrophage Inflammatory Proteins
  • Membrane Proteins
  • Receptors, Interferon
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • interferon-alpha A-D
  • Receptor, Interferon alpha-beta
  • Interferon-beta