A KAPOSIS SARCOMA-ASSOCIATED HERPESVIRUS-ENCODED CYTOKINE HOMOLOG (VIL-6) ACTIVATES SIGNALING THROUGH THE SHARED GP130 RECEPTOR SUBUNIT

The present studies analyzed the biologic activity of a gene product ( vIL-6) encoded by the recently discovered Kaposi's sarcoma-associated herpesvirus (KSHV) bearing 24.8% amino acid identity with human interl eukin-6 (huIL-6). Based on this similarity, we hypothesized that this viral homolog might trigger the JAK/STAT pathway, which typically is e ngaged by IL-6 and other cytokines, Activation of receptor-associated Janus tyrosine kinases (JAKs) results in the subsequent phosphorylatio n of signal transducers and activators of transcription (STATs) leadin g to nuclear entry and transcriptional regulation of target genes, Tre atment of HepG2 cells with culture medium containing recombinant KSHV- encoded vIL-6 led to rapid induction of JAK1 phosphorylation and a nuc lear DNA-binding activity found to contain STAT1 and STAT3. An antibod y to the IL-6 receptor (IL-6R) alpha subunit effectively neutralized t he response to huIL-6 but failed to block STAT activation by vIL-6. In contrast, an antibody reactive with the gp130 subunit of IL-6R abroga ted signaling of both responses. Moreover, a transfected cell line exp ressing human gp130 without IL-6R alpha exhibited a robust response to vIL-6 but not to huIL-6. These results demonstrate that KSHV encodes a cytokine that activates specific JAK/STAT signaling via interactions with the gp130 signal transducing subunit independently of the IL-6R alpha chain. This activity may have an impact on gp130-mediated signal ing in response to native cytokines and thereby influence disease path ogenesis upon KSHV infection.