Direct and mononuclear cell mediated effects on interleukin 6 production by glioma cells in infection with herpes simplex virus type 1

To clarify the mechanism of interleukin (IL)-6 elevation in the cerebrospin al fluid of viral meningitis and/or encephalitis patients, we investigated how herpes simplex virus type 1 (HSV1)-infection enhances IL-6 production i n human glioma cells (the U373MG and T98G cells). Although human glioma cel ls did not show enhanced IL-6 production by direct HSV1-infection, the cell -free supernatant from HSV1-stimulated mononuclear cells (MNC) culture and lipopolysaccharide, as a positive control, markedly elevated IL-6 productio n at both mRNA and polypeptide levels. Ultra violet-irradiated HSV1 induced the secretion of the IL-6 inducing factor(s) from MNC, whereas heat-inacti vated HSV1 did not show this activity. This finding indicated that the adso rption of virus on the surface of MNC may be sufficient for induction of se cretion. The supernatant from the culture of HSV1-stimulated MNC contained detectable amounts of IL-1 beta, tumor necrosis factor (TNF) alpha, interfe ron (IFN) gamma and IL-6, and its IL-6-inducing activity was inhibited only by anti-IL-1 beta antibodies. Moreover, recombinant IL-1 beta markedly enh anced IL-6 production in glioma cells with a concomitant elevation of its m RNA level. Taken together, the results suggest that in HSV1-infection of th e CNS, enhancement of IL-6 production in glial cells is mediated not by dir ect infection to glial cells but rather by IL-1 beta released from HSV1-sti mulated MNC. These findings may help elucidate the mechanisms underlying ce rebro-parenchymal inflammatory progression and repair in herpes simplex enc ephalitis. J. Med. Virol. 63:252-258, 2001. (C) 2001 Wiley-Liss, Inc.