Role of human herpesvirus 8 interleukin-6-activated gp130 signal transducer in primary effusion lymphoma cell growth and viability.

[primary effusion lymphoma]

Human herpesvirus 8 (HHV-8 ) infection is associated with Kaposi 's sarcoma , primary effusion lymphoma (PEL ), and multicentric Castleman 's disease . HHV-8 -encoded viral interleukin-6 (vIL-6 ) is believed to contribute to pathogenesis via proproliferative , antiapoptotic , and proangiogenic activities . In PEL cells , vIL-6 is produced in functional amounts during viral latency and promotes the growth of these cells , mediating its activity from the endoplasmic reticulum (ER ), where it is predominantly localized . This vIL-6 activity is dependent , in part , on its interaction with a splice variant of vitamin K epoxide reductase complex subunit 1 (VKORC 1 ), termed VKORC 1 variant 2 (VKORC 1 v 2 ). Here we report that the IL -6 signal transducer , gp 130 , which can support vIL-6 signaling from the ER , is also required for optimal PEL cell growth and viability . Levels of activated extracellular regulated kinases (ERKs ) 1 and 2 and signal transducer and activator of transcription 1 (STAT 1 ) and STAT 3 , phosphorylated following gp 130 stimulation , were reduced in gp 130 -depleted BCBL-1 and BC -1 cells . Diminished STAT activation was also detected in JSC-1 and BC -3 cells . Effects of gp 130 depletion on growth could be mimicked by short hairpin RNA targeting of ERKs 1 and 2 or by depletion of STAT 3 . Finally , inhibition of vIL-6 -gp 130 association specifically within the ER compartment suppressed cell proliferation and viability , mirroring the effects of gp 130 depletion . Combined , these data demonstrate that gp 130 , in addition to VKORC 1 v 2 , is essential for normal PEL cell growth and survival and that ER-localized vIL-6 -gp 130 interactions are critical for these activities . Targeting of intracellular vIL-6 -gp 130 interactions could potentially provide a means of PEL therapy .