Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 105, Issue 7, Pages 985-993Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI9232
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Funding
- NCI NIH HHS [R01 CA041268, CA79076, CA41268, R01 CA039621] Funding Source: Medline
- PHS HHS [KO1] Funding Source: Medline
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Macrophage inflammatory protein 1 alpha (MIP-1 alpha) 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-1 alpha and NK cell-produced IFN-gamma in shaping endogenous immune responses and defense in different compartments was examined. MIP-1 alpha deficiency profoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-gamma production in liver. MIP-1 alpha-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-1 alpha, NK cells, and IFN-gamma. The Mig response was also important for viral resistance. Thus, serum cytokine responses are insufficient; MIP-la 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.
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