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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Effects of MIP-1α and IFN-γ on resistance to MCMV. (a and b) MIP-1α+, MI...
Effects of MIP-1α and IFN-γ on resistance to MCMV. (a and b) MIP-1α+, MIP-1α–, IFN-γ–/– (IFN-γ–), and MIP-1α– IFN-γ– mice were uninfected or infected with 5 × 104 PFU MCMV at times indicated. Spleen (a) and livers (b) were harvested and homogenized for viral titer determinations as described in Methods. Limit of detection for the assay was 2 log PFU per gram of tissue. Means ± SE (n = 3) are shown. (c) Mice were uninfected or infected with 105 PFU (high dose) MCMV and monitored twice daily for survival. Results represent 1 of at least 2 experiments. Data shown represent the mean ± SE (n = 6).