A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense

J Clin Invest. 2000 Apr;105(7):985-93. doi: 10.1172/JCI9232.


Macrophage inflammatory protein 1alpha (MIP-1alpha) promotes natural killer (NK) cell inflammation in livers during murine cytomegalovirus (MCMV) infections, and NK cell-produced interferon gamma (IFN-gamma) contributes to defense against MCMV infections. A specific role for local NK cell IFN-gamma production, however, has not been established. The importance of MIP-1alpha and NK cell-produced IFN-gamma in shaping endogenous immune responses and defense in different compartments was examined. MIP-1alpha deficiency profoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-gamma production in liver. MIP-1alpha-independent IFN-gamma responses were observed in serum and spleen, and infection-induced elevations in blood NK cell populations occurred in absence of the factor, but peak liver expression of another chemokine, the monokine induced by IFN-gamma (Mig), depended upon presence of MIP-1alpha, NK cells, and IFN-gamma. The Mig response was also important for viral resistance. Thus, serum cytokine responses are insufficient; MIP-1alpha is critical for NK cell migration and IFN-gamma delivery to mediate protection; and Mig induction in tissues is a downstream protective response resulting from the process. These results define a critical chemokine-to-cytokine-to-chemokine cascade required for defense during a viral infection establishing itself in tissues.

Publication types

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

MeSH terms

  • Animals
  • Antigens / immunology
  • Antigens, Surface
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CXCL9
  • Chemokines, CXC / biosynthesis
  • Chemokines, CXC / genetics
  • Chemokines, CXC / immunology
  • Gene Expression
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / pathology
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Killer Cells, Natural / immunology*
  • Lectins, C-Type
  • Liver / immunology
  • Liver / pathology
  • Macrophage Inflammatory Proteins / genetics
  • Macrophage Inflammatory Proteins / immunology*
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Muromegalovirus / immunology*
  • NK Cell Lectin-Like Receptor Subfamily B
  • Proteins / immunology


  • Antigens
  • Antigens, Surface
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CXCL9
  • Chemokines, CXC
  • Cxcl9 protein, mouse
  • Lectins, C-Type
  • Macrophage Inflammatory Proteins
  • NK Cell Lectin-Like Receptor Subfamily B
  • Proteins
  • Interferon-gamma