The simultaneous expression of multiple cytokine genes was examined within the brain and peripheral organs of euthymic and congenic athymic mice during the course of lymphocytic choriomeningitis (LCM) induced by the intracranial inoculation of LCM virus. In euthymic mice, levels of TNF-alpha, IL-1 alpha, IL-6, and IL-1 beta mRNA in the brain increased early in infection and further increased with the progression of disease; the level of IFN-gamma mRNA was expressed at high levels late in infection and correlated with the onset of clinical disease. In the peripheral organs, TNF-alpha, IL-1 alpha, and IL-1 beta gene expression predominated early and then declined late in disease. In athymic mice (which do not develop LCM), expression of TNF-alpha, IL-1 alpha, IL-6, and IL-1 beta mRNA increased progressively in brain and peripheral organs from days 3 to 6 postinfection. The levels of these transcripts were significantly lower than those in infected euthymic animals. In euthymic mice, in situ hybridization revealed IFN-gamma-, TNF-alpha-, and IL-1 alpha-expressing cells throughout the inflammatory cell infiltrates associated with areas of LCMV nucleic acid. Therefore, in mice with LCM there is simultaneous expression of multiple cytokine genes, the pattern of which is distinct for brain vs peripheral organs and for euthymic vs athymic mice. The close spatiotemporal relationship between expression of cytokine genes and evolution of disease in brain implicate cytokines are not only key coordinators of the host response but also as possible mediators of neuropathology in LCM.