Tumor response is strongly enhanced by addition of tumor necrosis factor (TNF)-α to chemotherapy in local-regional perfusion. TNF primarily targets the endothelial lining of the tumor-associated vasculature, thereby improving permeability of the vascular bed. This augments uptake of the coadministered chemotherapeutic drug in the tumor. In vitro, however the high dose of TNF did not directly affect endothelial cells, indicating that other factors, most likely TNF-induced, are involved in the antivascular activities observed in vivo. This is supported by in vivo studies in our laboratory in which depletion of leukocytes resulted in loss of the antivascular activity of TNF. The present study examined the role of peripheral blood mononuclear cells (PBMCs) on endothelial cells by exposing them to TNF, interferon (IFN)-γ, and PBMCs. We observed morphological changes of the endothelial cells when exposed to TNF in combination with IFN. Endothelial cells became elongated, and gaps between the cells formed. Addition of PBMCs enhanced these alterations. The endothelial layer became disrupted with highly irregular-shaped cells displaying large gap formations. PBMCs also contributed to an increased permeability of the endothelial layer without augmenting apoptosis. Replacing PBMC by interleukin (IL)-1β produced similar effect with regard to inhibition of cell growth, morphological changes, and induction of apoptosis. Blocking IL-1β with a neutralizing antibody diminished the effects inflicted of PBMCs. These observations indicate that endogenously produced IL-1β by primed PBMCs plays an important role in the antivascular effect of TNF.

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doi.org/10.1385/CBB:44:1:157, hdl.handle.net/1765/63977
Cell Biochemistry and Biophysics
Department of Surgery

Seynhaeve, A.L.B, Vermeulen, C.E, Eggermont, A.M.M, & ten Hagen, T.L.M. (2006). Cytokines and vascular permeability: An in vitro study on human endothelial cells in relation to tumor necrosis factor-α-primed peripheral blood mononuclear cells. Cell Biochemistry and Biophysics, 44(1), 157–169. doi:10.1385/CBB:44:1:157