The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells. © 2013 Haas et al

Inhibition of Cowdria ruminantium infectious yield by interferons alpha and gamma in endothelial cells.

We have shown before that there is a positive correlation between resistance of cattle against Cowdria infection and early IFN production. Our in vitro studies demonstrated an activity of rBoIFN alpha 2C and rBoIFN gamma against Cowdria in bovine endothelial cells of brain microvasculature (BMEC). rBoIFN gamma is much more active in this respect than rBoIFN alpha 2C. These results suggest a role of IFNs in the resistance against the disease. Strikingly, in the same conditions rBoIFN alpha 2C has no effect on the yield of Cowdria from infected bovine endothelial cells of umbilical artery origin (BUEC). Similarly we showed that HuIFNa had no effect on the multiplication of Cowdria in human vein umbilical endothelial cells (HUVEC). We found no differences in the capacity of BUE and BME cells to bind rBoIFN alpha 2C. This may reflect a true difference between capillary and large blood vessels.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Inhibition of Cowdria ruminantium infectious yield by interferons alpha and gamma in endothelial cells.

We have shown before that there is a positive correlation between resistance of cattle against Cowdria infection and early IFN production. Our in vitro studies demonstrated an activity of rBoIFN alpha 2C and rBoIFN gamma against Cowdria in bovine endothelial cells of brain microvasculature (BMEC). rBoIFN gamma is much more active in this respect than rBoIFN alpha 2C. These results suggest a role of IFNs in the resistance against the disease. Strikingly, in the same conditions rBoIFN alpha 2C has no effect on the yield of Cowdria from infected bovine endothelial cells of umbilical artery origin (BUEC). Similarly we showed that HuIFNa had no effect on the multiplication of Cowdria in human vein umbilical endothelial cells (HUVEC). We found no differences in the capacity of BUE and BME cells to bind rBoIFN alpha 2C. This may reflect a true difference between capillary and large blood vessels.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Bovine and human endothelial cell growth on collagen microspheres and their infection with the rickettsia Cowdria ruminantium: prospects for cells and vaccine production.

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Metalloproteinas and TIMPs production by AIDS - Kaposi sarcoma derived cells

info:eu-repo/semantics/publishe

Constitutive release of metalloproteinase-9 (92-kd Type IV collagenase) by Kaposi's sarcoma cells

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Kaposi's sarcoma and herpesvirus 8: A word of caution [4]

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Biological response of endothelial cells and its modulation by cytokines: prospects for therapy and bioprocesses.

Endothelial cells are involved in important pathological situations. They could be the target for infectious processes as for example in Cowdriosis, an important disease in cattle due to the rickettsia Cowdria ruminantium prevalent in the south of the Sahara. They are also connected to angiogenic processes related to tumor invasion.Our results indicate that AIDS related Kaposi sarcoma cells may be of endothelial origin. We conclude from our data the mobility of those cells, related to the expression of the metalloproteinases (especially the 92 kD form of the enzyme), is an important factor in Kaposi saroma dissemination and is the main factor limiting the scale up of Cowdriosis vaccine production in Bovine Umbilical Endothelial Cell line. We showed that PMA and TNF increased the 92 kD Metallaproteinase and that TGFβ, produced in an inactive form in cultures of Human Umbilical Vein Endothelial Cells, is a potential inhibitor of Kaposi sarcoma spreading, and could also be useful in improving our process for Cowdria ruminantium vaccine production, since it reduces the sensitivity of the cells to mechanical stress without affecting significantly the overall infectious process.JOURNAL ARTICLEinfo:eu-repo/semantics/publishe