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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Figure 1

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Compartmental changes in NK cell populations. Blood (a and b) and liver ...
Compartmental changes in NK cell populations. Blood (a and b) and liver (c and d) leukocytes were prepared from C57BL/6-MIP-1α+/+ (MIP-1α+) or C57BL/6-MIP-1α–/– (MIP-1α–) mice either uninfected or infected with MCMV for 48 hours. Leukocytes were analyzed by flow cytometry as described in Methods. Both the percentage (a and c) and absolute number (b and d) of NK1.1+CD3– cells per milliliter of blood or NK1.1+TCR-β– cells per entire liver are shown. Data are means ± SE (n = 3). Compartmental changes represent results from 1 of 3 repetitive experiments. Differences between control MIP-1α+ and MIP-1α– are significant, AP < 0.01, BP < 0.001.