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J Pathol. 2011 Nov;225(3):378-89. doi: 10.1002/path.2962. Epub 2011 Aug 24.

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.

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1
HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

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.

PMID:
21984125
PMCID:
PMC3528401
DOI:
10.1002/path.2962
[Indexed for MEDLINE]
Free PMC Article
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