Tumor Necrosis Factor Alpha‐Stimulated Endothelium: An Inducer of Dendritic Cell Development from Hematopoietic Progenitors and Myeloid Leukemic Cells

Abstract

Especially when exposed to inflammatory stimuli, endothelial cells (EC) have been shown to promote the maturation of monocytes into dendritic cells (DC) and the long-term proliferation of CD34 + cells by constitutive cytokine production and direct cellular contact. We therefore hypothesized that cytokine-stimulated EC would induce hematopoietic progenitor cells to develop into mature dendritic cells. To test this theory, human CD34 + cells derived from cord blood or leukapheresis products were cultured with a monolayer of either interleukin (IL)-1β β, IL-4, or tumor necrosis factor (TNF)-α α-stimulated human umbilical cord EC. The cells in suspension were analyzed weekly over a period of 6 weeks. IL-1β β supported cell expansion, whereas IL-4 had no effect on cell expansion or DC differentiation. Only TNF-α α-stimulated EC induced the development of mature, allostimulatory DC with a high expression of CD83, HLA-DR, CD1a, and costimulatory molecules like CD80 and CD86. Acute myeloid leukemia cells from the cell line Kasumi-1 also developed DC-like features when cocultured with TNF-α α-stimulated EC. Direct contact between endothelial and progenitor cells increased the number of developing DC. Cell cycle analysis and apoptosis studies demonstrated a reduced G 2 M fraction, an increased S fraction, and a decrease in TNF-α α-dependent apoptosis of DC developing in the presence of endothelial cells. As shown by electron and confocal microscopic studies, intimate interactions between EC and DC occurred, resulting in the internalization of the developing DC within the EC monolayer and a bidirectional exchange of proteins. We conclude that, via the action of TNF-α α, inflamed human endothelium can induce CD34 + and leukemic cells to differentiate into dendritic cells.

Interleukin 32 promotes hematopoietic progenitor expansion and attenuates bone marrow cytotoxicity

“…In previous studies, we demonstrated that ECs stimulated by TNF-a induced the generation of dendritic cells from CD34 1 cells for more than 6 wk [3]. ILs, on the other hand, can also induce the proliferation of hematopoietic and myeloid progenitors [4].…”

“…Human umbilical cord ECs were harvested and cultured as described previously [3]. Confluent ECs of passages two to four were stimulated with IL-1b for 4, 8 and 16 h, and cells were harvested by collagenase (0.1% in PBS).…”

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double‐blind, randomized, placebo‐controlled trial

“…TNF acts in the early stages of the inflammatory process, during which it can costimulate T cell activation and induce the expression of interleukin-2 (IL-2), interferon-␥ receptors, proinflammatory cytokines such as IL-1 and IL-12, and proinflammatory chemokines such as IL-8 (14). TNF can also activate endothelial cells (15), potentiate differentiation of monocytes into osteoclasts (16), and induce release of matrix metalloproteinases by synovial fibroblast cells (17). The recognition that TNF has a pivotal role in inflammation and is present at elevated concentrations in psoriasis and PsA led to controlled clinical trials in which it was demonstrated that the TNF antagonists etanercept and infliximab had efficacy in both psoriasis and PsA (18)(19)(20)(21)(22).…”

Splenic Endothelial Cell Lines Support Development of Dendritic Cells from Bone Marrow

“…They support extended proliferation of DCs cultured out of bone marrow with IL-4 and TNF-␣. Fully differentiated HUVECs do not support DC development, whereas HUVECs treated with TNF-␣ support DC development from CD34 ϩ blood precursors [32]. DCs also mature by reverse transmigration through endothelium [33,34].…”