REGULATORY MECHANISMS OF MURANTES AND CRG-2 CHEMOKINE GENE INDUCTION IN CENTRAL-NERVOUS-SYSTEM GLIAL-CELLS BY VIRUS

In this report we characterize the induction mechanisms of two chemoki ne genes, MuRantes and crg-2, the murine homologs of human RANTES and IP-10, respectively, in primary rat astrocytes and microglia by the ne urotropic paramyxovirus, Newcastle Disease Virus (NDV). The time cours e for NDV induction of both MuRantes and crg-2 genes in astrocytes and microglia was similar, with peak mRNA expression at 10-12 h. Unlike c rg-2, MuRantes mRNA was not induced by IFN-gamma. MuRantes and crg-2 a re transcriptionally induced by noninfectious, UV-irradiated NDV in as trocytes and microglia, unlike TNF-alpha gene transcription, which is induced only by live NDV. These data indicate that signals generated t hrough virus-receptor interaction on the target cell surface suffice t o initiate MuRantes and crg-2 gene transcription in the absence of vir al replication. In astrocytes, MuRantes mRNA accumulation in response to NDV was completely blocked by tyrosine kinase inhibitors, and parti ally by PKC and PKA inhibitors, whereas crg-2 mRNA accumulation was si gnificantly inhibited by PKC inhibitors, but minimally or not affected by inhibitors of tyrosine kinase or PKA activity. These kinase inhibi tors also affected MuRantes and crg-2 gene transcription in similar pa tterns to those observed for mRNA levels, bur did not reduce the mRNA stability. Therefore, the signals required for mRNA accumulation appea r to operate at the level of transcription. Efficient transcription of MuRantes and crg-2 genes may require different sets of transcriptiona l proteins and enhancers that are regulated by different signaling pat hways activated by NDV. (C) 1995 Academic Press, Inc.