Kaposi's Sarcoma-Associated Herpesvirus Viral Interleukin-6 Signaling Upregulates Integrin β3 Levels and Is Dependent on STAT3

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of two B-cell lymphoproliferative diseases and Kaposi's sarcoma, an endothelial-cell-driven Cancer. KSHV viral interleukin-6 (vIL-6) is a viral homolog of human IL-6 (hIL-6) that is expressed in KSHV-associated malignancies. Previous studies have shown that the expression of the Integrin β3 (ITGB3) subunit is induced upon KSHV Infection. Here we report that KSHV vIL-6 is able to induce the expression of ITGB3 and increase surface expression of the αVβ3 Integrin heterodimer. We demonstrated using small interfering RNA (siRNA) depletion and inhibitor studies that KSHV vIL-6 can increase ITGB3 by inducing STAT3 signaling. Furthermore, we found that secreted vIL-6 is capable of inducing ITGB3 in endothelial cells in a paracrine manner. Importantly, the ability to induce ITGB3 in endothelial cells seems to be specific to vIL-6, as overexpression of hIL-6 alone did not affect levels of this Integrin. Our lab and Others have previously shown that vIL-6 can induce angiogenesis, and we investigated whether ITGB3 was involved in this process. We found that siRNA depletion of ITGB3 in vIL-6-expressing endothelial cells resulted in a decrease in adhesion to extracellular matrix proteins. Moreover, depletion of ITGB3 hindered the ability of vIL-6 to promote angiogenesis. In conclusion, we found that vIL-6 can singularly induce ITGB3 and that this induction is dependent on vIL-6 activation of the STAT3 signaling pathway.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of three human malignancies: multicentric Castleman's disease, primary effusion lymphoma, and Kaposi's sarcoma. Kaposi's sarcoma is a highly angiogenic tumor that arises from endothelial cells. It has been previously reported that KSHV Infection of endothelial cells leads to an increase of Integrin αVβ3, a molecule observed to be involved in the angiogenic process of several malignancies. Our data demonstrate that the KSHV protein viral interleukin-6 (vIL-6) can induce Integrin β3 in an intracellular and paracrine manner. Furthermore, we showed that this induction is necessary for vIL-6-mediated cell adhesion and angiogenesis, suggesting a potential role of Integrin β3 in KSHV pathogenesis and development of Kaposi's sarcoma.