Suppressors of cytokine signaling (SOCS) proteins are intracellular proteins that inhibit cytokine signaling in a variety of cell types. A number of viral infections have been associated with SOCS up-regulation; however, not much is known about the mechanisms regulating SOCS expression during viral infection. In this study, we have used two pathologically distinct intracerebral (i.c.) infection models to characterize temporal and spatial aspects of SOCS expression in the virus-infected CNS, and by employing various knockout mouse models, we have sought to identify regulatory mechanisms that may underlie a virus induced up-regulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual up-regulation of SOCS1/3 mRNA expression peaking at day 7 post infection (p.i.). In the LCMV model, SOCS mRNA was expressed in brain resident cells including astrocytes and some neurons, and for SOCS1 in particular this up-regulation was almost entirely mediated by IFN-γ produced by infiltrating T cells. Following infection with YF, we also found SOCS expression to be up-regulated in brain resident cells with a peak on day 7 p.i., but in this model, the up-regulation was only partially dependent on IFN-γ and T cells, indicating that at least one other mediator was involved in the up-regulation of SOCS following YF infection. We conclude that virus induced inflammation of the CNS is associated with up-regulation of SOCS1/3 mRNA expression in brain resident cells, and that at least two distinctive pathways can lead to this up-regulation.

IMPORTANCE: In the present report, we have studied the induction of SOCS1 and SOCS3 expression in the context of virus-induced CNS infection. We find that both a non-cytolytic and a cytolytic virus induce marked up-regulation of SOCS1 and-3 expression. Notably, the kinetics of the observed up-regulation follows that of activity within pro-inflammatory signalling pathways and, interestingly, type II IFN, which is also a key inducer of inflammatory mediators, seems to be essential in initiating this counter-inflammatory response. Another key observation is that not only cells of the immune system, but also CNS resident cells are actively involved in both the pro- and counter-inflammatory immune circuits; thus e. g. astrocytes up-regulates both CXCL10 and SOCS when exposed to type II IFN in vivo.