Requirements for the upregulation of interleukin-6 by herpes simplex virus-infected gingival fibroblasts

Interleukin (IL)-6 is an important proinflammatory and immunoregulatory cytokine expressed by various cells. This study examined the production of IL-6 by human gingival keratinocytes and gingival fibroblasts following herpes simplex virus (HSV) infection. Virus-cell interactions responsible for IL-6 induction by HSV-1 were determined. The amounts of IL-6 secreted by primary human gingival keratinocytes and gingival fibroblasts were determined using enzyme-linked immunosorbent assay. IL-6 expression in gingival fibroblasts was also determined using immunofluorescence staining. To further delineate the viral requirements for this induction, gingival fibroblasts were treated with antibody-neutralized viruses, UV- or heat-inactivated viruses or viral glycoprotein D of HSV-1 (gD-1). The results showed that infection of gingival fibroblasts, but not gingival keratinocytes, with HSV-1 induced production of IL-6. This modulation was blocked by neutralizing antibodies against HSV-1, suggesting that HSV-1 is required for this induction. Moreover, this induction was not abrogated when virus infectivity was destroyed by UV irradiation or heat, indicating that a complete viral life cycle is not required. Further studies showed that gD-1 alone was able to induce IL-6 secretion in gingival fibroblasts. Collectively, our data suggest that HSV-1 infection of gingival fibroblasts up-regulates production of IL-6 through a mechanism involving the interaction of gD-1 with cellular receptors.