Kaposi's sarcoma‐associated herpesviral IL‐6 and human IL‐6 open reading frames contain miRNA binding sites and are subject to cellular miRNA regulation

Abstract

Kaposi's sarcoma‐associated herpesvirus (KSHV) encodes a viral interleukin 6 (vIL‐6) that mimics many activities of human IL‐6 (hIL‐6). Both vIL‐6 and hIL‐6 play important roles in stimulating the proliferation of tumours caused by KSHV. Here, we provide evidence that a miRNA pathway is involved in regulation of vIL‐6 and hIL‐6 expression through binding sites in their open reading frames (ORFs). We show a direct repression of vIL‐6 by hsa‐miR‐1293 and hIL‐6 by hsa‐miR‐608. The repression of vIL‐6 by miR‐1293 was reversed by disruption of the vIL‐6 miR‐1293 seed match through the introduction of point mutations. In addition, expression of vIL‐6 or hIL‐6 in KSHV‐infected cells could be enhanced by transfection of the respective miRNA inhibitors. In situ hybridization of human lymph node sections revealed that miR‐1293 is primarily expressed in the germinal centre but is deficient in the mantle zone of lymph nodes, where the expression of vIL‐6 is often found in patients with KSHV‐associated multicentric Castleman's disease, providing evidence of an anatomical correlation. Taking these factors together, our study indicates that IL‐6 expression can be regulated by miRNA interactions in its ORF and provides evidence for the role of these interactions in the pathogenesis of KSHV‐associated diseases. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.