KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) encodes viral IL-6 (vIL-6), a homolog of human IL-6.
• vIL-6 expression is implicated in the pathogenesis of KSHV-related lymphoproliferative disorders.
• vIL-6 mimics IL-6 activities, including cell growth stimulation and JAK/STAT pathway activation.

Purpose of the Study:

• To investigate whether vIL-6 signals through distinct IL-6 response elements (IL-6 REs) controlled by different pathways.
• To compare the signaling capabilities of vIL-6 with those of human IL-6.

Main Methods:

• Analysis of vIL-6 activation of STAT1/3- and STAT5-dependent Type II IL-6 REs.
• Assessment of vIL-6-induced transcriptional activation via a Type I IL-6 RE binding C/EBP.
• Examination of vIL-6 activation of the IL-6 response element in the c-jun promoter (RE-IL-6).

Main Results:

• vIL-6 activates both STAT1/3- and STAT5-dependent Type II IL-6 REs.
• vIL-6 induces transcriptional activation via a Type I IL-6 RE, indicating Ras-MAP kinase pathway induction.
• vIL-6 activates the c-jun promoter RE-IL-6, requiring Ets- and Cre-like sites, suggesting stimulation of a novel serine/threonine kinase pathway.

Conclusions:

• vIL-6 stimulates all known IL-6-induced signaling pathways.
• vIL-6 may contribute to KSHV-related disease progression by activating growth and anti-apoptotic pathways.
• vIL-6 can bypass IL-6 receptor alpha (IL-6Ralpha) dependency, potentially overcoming cellular resistance mechanisms.