The Kaposi's sarcoma-associated herpesvirus (KSHV)-induced 5-lipoxygenase-leukotriene B4 cascade plays key roles in KSHV latency, monocyte recruitment, and lipogenesis.

[primary effusion lymphoma]

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 2 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 :e 1000777 , 2010 [doi :10 .1371 /journal .ppat .1000777 ]). Here , we evaluated the role of 5 -lipoxygenase (5 LO ) and its chemotactic metabolite leukotriene B 4 (LTB 4 ) in KSHV biology . Abundant staining of 5 LO was detected in human KS tissue sections . We observed elevated levels of 5 LO and high levels of secretion of LTB 4 during primary KSHV infection of endothelial cells and in PEL B cells (BCBL-1 and BC -3 cells ). Blocking the 5 LO /LTB 4 cascade inhibited viral latent ORF 73 , immunomodulatory K 5 , viral macrophage inflammatory protein 1 (MIP -1 ), and viral MIP -2 gene expression , without much effect on lytic switch ORF 50 , immediate early lytic K 8 , and viral interferon-regulatory factor 2 gene expression . 5 LO inhibition significantly downregulated latent viral Cyclin and latency-associated nuclear antigen 2 levels in PEL cells . 5 LO /LTB 4 inhibition downregulated TH 2 -related cytokine secretion , elevated TH 1 -related cytokine secretion , and reduced human monocyte recruitment , adhesion , and transendothelial migration . 5 LO /LTB 4 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 5 LO /LTB 4 play important roles in KSHV biology and that effective inhibition of the 5 LO /LTB 4 pathway could potentially be used in treatment to control KS /PEL .

Diseases
Validation

Diseases presenting "growth factors" symptom

achondroplasia

alexander disease

aromatase deficiency

cholangiocarcinoma

dentin dysplasia

dentinogenesis imperfecta

dystrophic epidermolysis bullosa

kallmann syndrome

oligodontia

oral submucous fibrosis

primary effusion lymphoma

scrub typhus

severe combined immunodeficiency

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