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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-1[alpha] 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.

Copyright (C) 2000 The American Society for Clinical Investigation, Inc.