Pivotal Advance: Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded microRNA specifically induce IL-6 and IL-10 secretion by macrophages and monocytes

Abstract

Macrophages are an important source of inflammatory cytokines generated during the innate immune response,but in the microenvironment of certain tumors,macrophages promote tumor progression through their preferential secretion of cytokines that support tumor cell growth and suppress antitumoral immune responses. KSHV is the causative agent of KS and lymphomas preferentially arising in immuno compromised patients, and specific cytokines, including IL-6 and IL-10, have been implicated in KSHV-associated cancer pathogenesis. However, the contribution of KSHV-infected macrophages to the cytokine milieu within KSHV-related tumors is unclear. We found that individual KSHV-encoded miRNA induce IL-6 and IL-10 secretion independently and additively by murine macrophages and human myelomonocytic cells. Bioinformatics analysis identified KSHV miRNA binding sites formiR-K12-3 and miR-K12-7 within the 3'UTR of the basic region/leucine zipper motif transcription factor C/EBPbeta, a known regulator of IL-6 and IL-10 transcriptional activation.Subsequent immunoblot analyses revealed that miR-K12-3 and miR-K12-7 preferentially reduce expression of C/EBPbeta p20 (LIP), an isoform of C/EBPbeta known to function as a negative transcription regulator. In addition,RNA interference specifically targeting LIP induced basal secretion of IL-6 and IL-10 by macrophages.Taken together, these data support a role for KSHV miRNA in the programming of macrophage cytokine responses in favor of KSHV-related tumor progression.

High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

“…Despite the inability to monitor trends in serum vIL-6 Ͻ 1560 pg/mL, in cases where serum vIL-6 was detectable, levels decreased in parallel with the improvement in clinical symptoms and increased with worsening inflammatory symptoms, consistent with an important role for vIL-6 in KSHV-MCD. Serum IL-10, which can be upregulated by KSHV miR-K12-7, 48 also paralleled symptomatology in patients receiving AZT/VGC. Estimated overall survival of study subjects was 86% at the end of 4 years.…”

A Kaposi's Sarcoma-Associated Herpesvirus-Encoded Ortholog of MicroRNA miR-155 Induces Human Splenic B-Cell Expansion in NOD/LtSz-scid IL2Rγ null Mice

“…Here, we show that miR-K12-11 expression alone induces human B-cell proliferation in the context of hematopoiesis. Other KSHV miRNAs have been found to repress proapoptotic, antiangiogenic, and immunostimulatory factors, thereby potentially contributing to lymphomagenesis, a notion that is testable using our NOD/LtSz-scid IL2R␥ null mouse model (20,23,32,41,45,49,60).…”

“…KSHV latent proteins regulate cellular pathways to inhibit apoptosis, induce cellular proliferation, and modulate cytokine responses, but the roles of KSHV miRNAs in pathogenesis are still being characterized (for a review, see reference 12). Insights into the pathogenic nature of these viral miRNAs have been provided by findings that they target host genes involved in tumorigenesis, cellular differentiation, immunity, and apoptosis (23,32,41,45,60).…”

“…IL-6 and IL-10 are cytokines that function in an autocrine and paracrine fashion to promote the proliferation and survival of B cells, including PEL (1,16,24,25,37,43,48). To our knowledge, there has been no reported correlation between KSHV B-cell lymphomagenesis and C/EBP␤ repression, but a recent study bioinformatically predicted that C/EBP␤ could be targeted by multiple KSHV miRNAs, including miR-K12-11 (41). Qin et al also showed that these KSHV miRNAs induce IL-6 and IL-10 production in monocytes and macrophages but did not confirm that this was due to direct miRNA regulation of C/EBP␤.…”

KSHV Paracrine Effects on Tumorigenesis

“…The recruited and activated infiltrating inflammatory cells in turn release inflammatory cytokines (IC), such as IFN-, IL-1 , TNF-, and IL-6, which are essential for the activation and proliferation of cells comprised in the KS lesions. Interestingly, these cytokines can induce uninfected endothelial cells to acquire the phenotypic and functional features of KS spindle cells Monini et al, 1999;Qin et al, 2010;Samaniego et al, 1995;Sirianni et al, 1998;Stürzl et al, 1995). In accordance, these cytokines are also detected in vivo at increased concentrations in the serum of patients with all forms of KS and of individuals at high risk for KS (Emilie et al, 1990;Ensoli et al, 1992;Fuchs et al, 1989;Hober et al, 1989).…”