Theiler's virus infection provokes the overexpression of genes coding for the chemokine Ip10 (CXCL10) in SJL/J murine astrocytes, which can be inhibited by modulators of estrogen receptors

Theiler's murine encephalomyelitis virus (TMEV) induces demyelination in susceptible strains of mice (SJL/J) through an immunopathological process that is mediated by CD4(+) Th1 T cell. These T cells are chemoattracted to the central nervous system by chemokines. Hence, in this study, we focused on the production of the chemokine interferon-gamma-inducible protein 10 kDa, or IP-10/CXCL10, by cultured SJL/J mouse astrocytes infected with the BeAn strain of TMEV and its capacity to attract activated T cells. The analysis of the whole murine genome by DNA hybridization with cRNAs from mock- and TMEV-infected cultures revealed the upregulation of six sequences that potentially encode for CXCL10. This increased CXCL10 expression was validated by PCR and qPCR. The presence of this chemokine was further demonstrated by enzyme-linked immunoassay (ELISA). Significantly, astrocytes from BALB/c mice, a strain resistant to demyelination, did not produce CXCL10. The secreted CXCL10 was biologically active, inducing chemoattraction of activated lymphocytes. The inflammatory cytokines, IL-1 alpha, IFN-gamma, and TNF-alpha, were strong inducers of CXCL10 in astrocytes. Serum from TMEV-infected SJL/J but not BALB/c mice contains CXCL10, the levels of which peak at the onset of the clinical disease. Finally, this in vitro inflammation model was fully inhibited by 17 beta-estradiol and four selective estrogen receptor modulators, as demonstrated by ELISA and qPCR.