A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense
Thais P. Salazar-Mather, … , Thomas A. Hamilton, Christine A. Biron
Thais P. Salazar-Mather, … , Thomas A. Hamilton, Christine A. Biron
Published April 1, 2000
Citation Information: J Clin Invest. 2000;105(7):985-993. https://doi.org/10.1172/JCI9232.
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Article

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

Abstract

Macrophage inflammatory protein 1α (MIP-1α) promotes natural killer (NK) cell inflammation in livers during murine cytomegalovirus (MCMV) infections, and NK cell–produced interferon γ (IFN-γ) contributes to defense against MCMV infections. A specific role for local NK cell IFN-γ production, however, has not been established. The importance of MIP-1α and NK cell–produced IFN-γ in shaping endogenous immune responses and defense in different compartments was examined. MIP-1α deficiency profoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-γ production in liver. MIP-1α–independent IFN-γ 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-γ (Mig), depended upon presence of MIP-1α, NK cells, and IFN-γ. The Mig response was also important for viral resistance. Thus, serum cytokine responses are insufficient; MIP-1α is critical for NK cell migration and IFN-γ 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.

Authors

Thais P. Salazar-Mather, Thomas A. Hamilton, Christine A. Biron

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Requirements for IFN-γ and Mig gene expression. (a and b) Liver RNA was ...
Requirements for IFN-γ and Mig gene expression. (a and b) Liver RNA was isolated from MIP-1α+, MIP-1α-, or IFN-γ– mice that were uninfected or infected with MCMV. (a) Total RNA was analyzed by Northern blot hybridization. Results represent 1 of 3 experiments. (b) Relative quantitative RT-PCR was carried out with Competimers for 18-S rRNA as internal controls. (c) Total liver RNA was prepared from MIP-1α+ and MIP-1α– mice administered control IgG (denoted as C) or anti-CD3 (α-CD3) at 3 hours before harvest. RNA was prepared and analyzed by relative quantitative RT-PCR as above. (d) Liver RNA was isolated from mice that were uninfected or infected with MCMV, with or without NK cell depletions. Mice were C57BL/6 or C57BL/6-SCID mice treated with control IgG (denoted as C), anti-NK1.1, or anti-AGM1 24 hours before infection. RNA was analyzed by relative quantitative RT-PCR as above. b–d show ethidium bromide–stained gel of amplified products, representing 1 of 3 experiments (see Table 1 for quantitation of results and Methods for details of procedures).