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. 2004 Oct 10;328(1):7-18.
doi: 10.1016/j.virol.2004.07.008.

Kaposi's sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation

Patrick A Carroll  1 , Elizabeth Brazeau, Michael Lagunoff
Affiliations

Kaposi's sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation

Patrick A Carroll et al. Virology. .

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is necessary for KS, a highly vascularized tumor predominated by endothelial-derived spindle cells that express markers of lymphatic endothelium. Following KSHV infection of TIME cells, an immortalized human dermal microvascular endothelial cell (DMVEC) line, expression of many genes specific to lymphatic endothelium, including VEGFR3, podoplanin, LYVE-1, and Prox-1, is significantly increased. Increases in VEGFR3 and podoplanin protein are also demonstrated following latent infection. Examination of cytokine secretion showed that KSHV infection significantly induces hIL-6 while strongly inhibiting secretion of IL-8, a gene product that is decreased by differentiation of blood to lymphatic endothelial cells. These studies support the hypotheses that latent KSHV infection of blood endothelial cells drives their differentiation to lymphatic endothelial cells.

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Figures

Fig. 1
Fig. 1
KSHV infection of TIME cells induces specific markers of lymphatic endothelial cells. (A) Depicted is the fold change of LEC-specific transcripts in KSHV-infected TIME cells compared to UV-irradiated virus-treated cells at 48 h postinfection as determined by real-time RT-PCR (N = 3–5). All values were normalized to GAPDH expression and error bars represent the standard error of the mean. (B) Shown is a representational gel of Prox-1 and GAPDH mRNA amplification by semi-quantitative RT-PCR from mock- and KSHV-infected TIME cells. (C) Western blot analysis of VEGFR3 podoplanin in mock- and KSHV-infected TIME cells. Cox1 is included as a loading control.
Fig. 2
Fig. 2
Podoplanin expression is increased in latently infected TIME cells. TIME cells that are >90% latently infected and <1% lytically infected with KSHV and matched mock-infected cells were fixed 72 h after infection and co-stained with anti-podoplanin antibody (green), anti-LANA (red), and DAPI (blue) to stain the nuclei. Only those infected cells that express LANA exhibit cytoplasmic membrane staining for podoplanin.
Fig. 3
Fig. 3
KSHV infection of TIME cells alters transcripts involved in angiogenesis. Depicted is the fold change of angiogenesis-related transcripts in KSHV-infected TIME cells compared to UV-irradiated virus treated cells at 48 h postinfection as determined by real-time RT-PCR (N = 3–5). All values were normalized to GAPDH expression and error bars represent the standard error of the mean.
Fig. 4
Fig. 4
KSHV infection of endothelial cells alters cytokine production and secretion. (A) Depicted is the fold change of IL6 and IL8 transcripts in KSHV-infected TIME cells compared to UV-irradiated virus treated cells at 48 h postinfection as determined by real-time RT-PCR (N = 3). All values were normalized to GAPDH expression and error bars represent the standard error of the mean. (B) A cytokine antibody array was used to monitor secreted cytokines from KSHV-infected and mock-infected primary human DMVECs by probing the antibody-spotted membrane with diluted supernatants from 48 to 96 h postinfection.
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