Peripheral Blood Mononuclear Cells Induce Programmed Cell Death in Human Endothelial Cells and May Prevent Repair: Role of Cytokines

Abstract

Human umbilical vein endothelial cells (HUVECs) undergo programmed cell death (apoptosis) after coculture with peripheral blood mononuclear cells (PBMCs) preactivated by ionizing radiation (IR) or by bacterial endotoxin (lipopolysaccharide [LPS]). Cell-to-cell contact-mediated apoptosis could be blocked in both cases by anti–tumor necrosis factor-α (anti–TNF-α) monoclonal antibody MAK195 and also by the antagonistic cytokine interleukin-10 (IL-10). Cell-free PBMC supernatants from both preactivation treatments were sufficient to trigger endothelial apoptosis. In contrast, MAK195 and IL-10 were found to be ineffective in this system, suggesting a TNF-α–independent mechanism. However, N-Acetylcystein, an antioxidant, fully abrogated programmed cell death mediated by the supernatant of IR-treated PBMCs, but not of LPS-treated PBMCs. Additionally, we found that coculture and cell-free supernatants of preactivated as well as untreated PBMCs caused cell cycle arrest in proliferating EC in G0/1 , which could be relieved by IL-10, but not by anti–TNF-α. Further analysis showed that transforming growth factor-β, which was constitutively expressed in the supernatant of PBMCs, namely lymphocytes, was responsible for this. These data suggest a pathophysiologic model in which preactivated PBMCs cause EC damage and may prevent blood vessel repair by arresting the proliferation of ECs. This could contribute to the understanding of various clinical endothelial complications that occur after irradiation as well as in cases of endotoxemia or related inflammatory states.

Effects of Infliximab on Apoptosis and Reverse Signaling of Monocytes from Healthy Individuals and Patients with Crohn’s Disease

“…The prolonged remission of some CD patients after a single infusion of infliximab 18 suggests that infliximab, in addition to neutralizing soluble TNF, might exert more longlasting effects by interacting directly with T cells and/or macrophages via membrane TNF, which is known to be expressed by these cells. 19,20 Indeed, previous studies demonstrated that infliximab induces apoptosis of activated but not resting T cells and also of lamina propria T lymphocytes of patients with active CD. 14,15 Furthermore, Lugering et al 8 reported that infliximab induces apoptosis of peripheral blood monocytes from both healthy controls and patients with chronic active CD.…”

Entry and Integration of Transplanted Hepatocytes in Rat Liver Plates Occur by Disruption of Hepatic Sinusoidal Endothelium

“…Nondestructive endothelial cell separations may involve cytoskeletal alterations, 29 as well as increased endothelial permeability. It is well established that cytokines capable of affecting endothelial cells, e.g., interleukins and tumor necrosis factor ␣ may be released by infiltrating macrophages, 30 activated Kupffer cells, 23 or even endothelial cells themselves. 24 Endothelial disruption may involve release of free radicals and induction of oxidative stress mediated by xanthine oxidase activity in Kupffer and endothelial cells as previously documented.…”

“…31,32 Perfusionreperfusion injury arising from cell embolizations as discussed previously may additionally cause cytokine release, including secondary decline in sinusoidal blood flow, 23 depletion of antioxidant glutathione activity, 33 and finally endothelial disruption. 30 Certainly, in response to hypoxia and other stimuli, parenchymal cells release specific factors, such as VEGF/VPF, hepatocyte growth factor, transforming growth factor ␣, and fibroblast growth factor. 34,35 Under hypoxic conditions, endothelial cells are known to exhibit VEGF/VPF receptor up-regulation.…”

Inflammation, endothelium, and coagulation in sepsis

“…LPS has been shown to induce endothelial apoptosis in vitro and also, although not in all studies, in vivo [43]. Interaction with other cells may influence endothelial apoptosis; for example, LPS-activated monocytes have been shown to contribute to endothelial apoptosis in vitro [44]. Endothelial apoptosis has been shown to contribute to a procoagulant state in vitro [45].…”