Induction of the CXCL1 (KC) chemokine in mouse astrocytes by infection with the murine encephalomyelitis virus of Theiler

In the present study, we focused on the production of the chemokine CXCL1, also termed KC, by cultured Theiler murine encephalomyelitis virus (TMEV)-infected mouse astrocytes. cRNA from mock- and TMEV-infected cells was hybridized to the Affymetrix murine genome U74v2 DNA microarray. Hybridization data analysis demonstrated upregulation of two sequences coding for IL-8 and related to the GRO I oncogene MGSA. The murine counterpart of the above human genes has been reported to be the chemokine CXCL1 or KC, and therefore we studied its regulation, confirming its mRNA increase by Northern blots. The presence of CXCL1 in the supernatants of infected cells was further demonstrated by a specific ELISA and its intracellular accumulation by flow cytometry. This secreted CXCLI was biologically active in a non species-specific way as it induces chemoattraction on human neutrophils and monocyte/macrophages, but not on CD3 positive lymphocytes. Its induction does not follow the MAP kinase pathway which transcripts are decrease in infected cells compared with uninfected astrocytes. Two inflammatory cytokines, IL-1 alpha and TNF-alpha, which are also induced by TMEV in astrocytes, were potent inducers of CXCL1. Nevertheless, both mechanisms of induction follow different pathways as antibodies to both cytokines fail to inhibit TMEV-induced CXCLI upregulation. Spinal cords but not brains from TMEV-infected SJL/J animals contain CXCLI at the start of clinical signs of the disease. As no CXCLI induction can be detected neither in cultured BALB/c astrocytes nor in nervous tissue, we propose an important role for CXCLI in this experimental model of multiple sclerosis as a chemoattractant of destructive immune cells. (c) 2006 Elsevier Inc. All rights reserved.