Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Down-Regulates IL-22R1 Expression through a Cis-Acting Element within the Promoter Region

Ling Su,Qingjiao Liao,Yang Wu,Xulin Chen,Maria G Masucci

doi:10.1371/journal.pone.0019106

Ling Su, Qingjiao Liao + Show 3 more

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https://doi.org/10.1371/journal.pone.0019106

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Journal: PLoS ONE	Publication Date: Apr 22, 2011
Citations: 53	License type: CC BY 4.0

Affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is considered to be a necessary, but not sufficient, causal agent of Kaposi's sarcoma (KS). All forms of KS are characterized by the proliferation of spindle-shaped cells, and most (>90%) spindle cells from KS lesions are latently infected with KSHV. During KSHV latency, only a few viral genes are expressed. Among those latent genes, the ORF 73 gene encodes the latency-associated nuclear antigen (LANA), which is critical for the establishment and maintenance of the latent KSHV infection. Much evidence suggests that many cytokines can increase the frequency and aggressiveness of KS. In this study, a microarray analysis of KS and normal tissues revealed that multiple cytokines and cytokine receptors are regulated by KSHV latent infection. Of special interest, IL-22R1 transcript level was found to be down-regulated in the KS tissue. To study the possible regulation of IL-22R1 by LANA, the IL-22R1 promoter was constructed and found to contain a LANA-binding site (LBS). LANA was demonstrated to down-regulate IL-22R1 expression via direct binding to the LBS located within the IL-22R1 promoter region. Furthermore, KSHV latently infected cells showed an impaired response to IL-22 stimulation. These results suggest that LANA can regulate host factor expression by directly binding to a cis-acting element within the factor's promoter to benefit latent viral infection and suppression of the antiviral immune response.

Highlights

Kaposi’s sarcoma (KS) is a multicentric angioproliferative disorder that frequently involves the skin [1]
To further identify cellular genes regulated upon the formation of a KS lesion, gene expression profiles were compared between Kaposi sarcoma and normal skin tissues by cDNA-microarray
Kaposi’s sarcomaassociated herpesvirus (KSHV) is the causal agent of Kaposi’s sarcoma (KS) and all forms of KS are characterized by the proliferation of spindleshaped cells

Summary

Introduction

Kaposi’s sarcoma (KS) is a multicentric angioproliferative disorder that frequently involves the skin [1]. KSHV is associated with primary effusion lymphoma (PEL) and a subset of multicentric Castleman’s disease [2]. In early-stage KS, large numbers of inflammatory cells, including lymphocytes and macrophages, are recruited into KS lesions [4]. These cells produce high levels of proinflammatory cytokines and growth factors. Cytokines produced by inflammatory cells induce normal endothelial cells to acquire the features of KS spindle cells and to induce production of angiogenic factors [5]. The evidence suggests that cytokines can increase the frequency and aggressiveness of KS by enhancing the effect of angiogenic factors or by reactivating KSHV reinfection, which is etiologically closely associated with KS [8]

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