Type 1 interferon (IFN) receptor gene knockout (IFNAR(-/-)) mouse embryo fibroblasts (MEFs) are more susceptible to and productive of West Nile virus (WNV) and produce less type 1 IFN than WNV-infected wild-type (wt) MEFs. WNV infection of IFNAR(-/-) MEFs induced activation of a p65/p50 heterodimer of nuclear factor (NF)- kappa B and up-regulation of cell-surface expression of major histocompatibility complex class I (MHC-I) molecules. WNV infection of wt MEFs resulted in a greater up-regulation of MHC-I than did infection of IFNAR(-/-) MEFs because of the action of endogenous type 1 IFN production. IFN- beta -treatment of wt MEFs did not activate NF- kappa B but did up-regulate cell-surface MHC-I expression. The WNV-induced NF- kappa B activation was partially abrogated by the serine protease inhibitor N-benzoyl-l-tosyl-l-phenylalanine, which also abrogated the up-regulation of MHC-I. Thus, we demonstrate 2 pathways for WNV-induced up-regulation of MHC-I, a WNV-induced NF- kappa B-dependent, IFN-independent pathway and an NF- kappa B-independent, IFN-dependent pathway.