The Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Induced 5-Lipoxygenase-Leukotriene B4 Cascade Plays Key Roles in KSHV Latency, Monocyte Recruitment, and Lipogenesis
Identifieur interne : 002446 ( Main/Exploration ); précédent : 002445; suivant : 002447The Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Induced 5-Lipoxygenase-Leukotriene B4 Cascade Plays Key Roles in KSHV Latency, Monocyte Recruitment, and Lipogenesis
Auteurs : Neelam Sharma-Walia ; Karthic Chandran ; Kinjan Patel ; Mohanan Valiya Veettil ; Alexandru MargineanSource :
- Journal of Virology [ 0022-538X ] ; 2014.
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS lesions are characterized by endothelial cells with multiple copies of the latent KSHV episomal genome, lytic replication in a low percentage of infiltrating monocytes, and inflammatory cytokines plus growth factors. We demonstrated that KSHV utilizes inflammatory cyclooxygenase 2/prostaglandin E2 to establish and maintain latency (Sharma-Walia, N., A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog 6:e1000777, 2010 [doi:
Url:
DOI: 10.1128/JVI.02786-13
PubMed: 24335295
PubMed Central: 3911547
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Induced 5-Lipoxygenase-Leukotriene B4 Cascade Plays Key Roles in KSHV Latency, Monocyte Recruitment, and Lipogenesis</title>
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<author><name sortKey="Veettil, Mohanan Valiya" sort="Veettil, Mohanan Valiya" uniqKey="Veettil M" first="Mohanan Valiya" last="Veettil">Mohanan Valiya Veettil</name>
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<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
<idno type="eISSN">1098-5514</idno>
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<front><div type="abstract" xml:lang="en"><p>Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS lesions are characterized by endothelial cells with multiple copies of the latent KSHV episomal genome, lytic replication in a low percentage of infiltrating monocytes, and inflammatory cytokines plus growth factors. We demonstrated that KSHV utilizes inflammatory cyclooxygenase 2/prostaglandin E<sub>2</sub>
to establish and maintain latency (Sharma-Walia, N., A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog 6:e1000777, 2010 [doi:<ext-link ext-link-type="uri" xlink:href="http://10.1371/journal.ppat.1000777">10.1371/journal.ppat.1000777</ext-link>
]). Here, we evaluated the role of 5-lipoxygenase (5LO) and its chemotactic metabolite leukotriene B4 (LTB4) in KSHV biology. Abundant staining of 5LO was detected in human KS tissue sections. We observed elevated levels of 5LO and high levels of secretion of LTB4 during primary KSHV infection of endothelial cells and in PEL B cells (BCBL-1 and BC-3 cells). Blocking the 5LO/LTB4 cascade inhibited viral latent ORF73, immunomodulatory K5, viral macrophage inflammatory protein 1 (MIP-1), and viral MIP-2 gene expression, without much effect on lytic switch ORF50, immediate early lytic K8, and viral interferon-regulatory factor 2 gene expression. 5LO inhibition significantly downregulated latent viral Cyclin and latency-associated nuclear antigen 2 levels in PEL cells. 5LO/LTB4 inhibition downregulated TH2-related cytokine secretion, elevated TH1-related cytokine secretion, and reduced human monocyte recruitment, adhesion, and transendothelial migration. 5LO/LTB4 inhibition reduced fatty acid synthase (FASN) promoter activity and its expression. Since FASN, a key enzyme required in lipogenesis, is important in KSHV latency, these findings collectively suggest that 5LO/LTB4 play important roles in KSHV biology and that effective inhibition of the 5LO/LTB4 pathway could potentially be used in treatment to control KS/PEL.</p>
</div>
</front>
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<tree><noCountry><name sortKey="Chandran, Karthic" sort="Chandran, Karthic" uniqKey="Chandran K" first="Karthic" last="Chandran">Karthic Chandran</name>
<name sortKey="Marginean, Alexandru" sort="Marginean, Alexandru" uniqKey="Marginean A" first="Alexandru" last="Marginean">Alexandru Marginean</name>
<name sortKey="Patel, Kinjan" sort="Patel, Kinjan" uniqKey="Patel K" first="Kinjan" last="Patel">Kinjan Patel</name>
<name sortKey="Sharma Walia, Neelam" sort="Sharma Walia, Neelam" uniqKey="Sharma Walia N" first="Neelam" last="Sharma-Walia">Neelam Sharma-Walia</name>
<name sortKey="Veettil, Mohanan Valiya" sort="Veettil, Mohanan Valiya" uniqKey="Veettil M" first="Mohanan Valiya" last="Veettil">Mohanan Valiya Veettil</name>
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