Tumor necrosis factor/cachectin increases permeability of endothelial cell monolayers by a mechanism involving regulatory G proteins.

Abstract

Endothelium serves as the cellular barrier retaining blood components within the intravascular space (1). This function is compromised in many pathophysiologic states . Most notably, the profound alterations in endothelial cell barrier function specifically induced by host mediators released in response to bacterial LPS contribute importantly to the pathogenesis of endotoxic/septic shock.The cytokine tumor necrosis factor/cachectin (TNF), one of several host mediators synthesized by macrophages after exposure to LPS, has been shown to be a central mediator of the shock state in Gram-negative sepsis (2, 3). Infusion ofTNF into animals produces many of abnormalities characteristic of Escherichia coli/LPS toxemia, including vascular leakage due to loss of barrier function (2, 4). Vascular endothelium has been shown to be a direct target for the action ofTNF, which causes modulation of many endothelial cell functions, such as coagulant activity and immunologic properties (2). Recent studies (5-7) suggest that the normal barrier function of the endothelium can also be altered directly by TNF. These considerations have led us to examine the effect of TNF on endothelial permeability. The results indicate that within 1-3 h after exposure to TNF, permeability of cultured endothelial monolayers to macromolecular and lower molecular weight solutes increased markedly ; this effect was temporally correlated with alterations in the cytoskeleton and cell shape, and the formation of intercellular gaps. Pertussis toxin blocked both the change in cell shape/cytoskelton and the increase in permeability, indicating that a pertussis toxin-sensitive G protein critically regulates this TNFinduced response. In contrast, other TNFinduced changes in endothelial cell function, such as perturbation of certain cell surface coagulant properties, were not affected by pertussis toxin. These data suggest the presence of more than one TNFdependent signal transduction pathway within endothelial cells: a pathway involving a pertussis toxin-sensitive G protein leads to increased vascular permeability, whereas, a separate mechanism underlies the modulation of other cellular properties by TNF.

Mechanisms of differential regulation of interleukin‐6 mRNA accumulation by tumor necrosis factor alpha and lymphotoxin during monocytic differentiation

“…As presented here, neither cytokine modulates accumulation of the IL-6 mRNA by interacting with preexisting transcription factors (either repressors or activators) since both TNF alpha and LT require de novo protein synthesis to exert their effects. Induction of transcriptional activators such as AP-1, which has recently been shown to mediate TNF alpha-induced collagenase gene expression in fibroblasts [30] or of Gbinding proteins known to mediate effects of TNF alpha on endothelial cells [31], might also be involved in LT and TNF alpha-modulated IL-6 gene expression. In uninduced as in induced monocytes, IL-6 mRNA is under control of short-lived destabilizers leading to superinduction of IL-6 message as soon as protein synthesis is inhibited.…”

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

“…2 TNF-a induces tissue factor production and increases vascular permeability and procoagulant activity on endothelial cells. [3][4][5] Unfortunately, recombinant TNF-a has limited clinical utility because of predictable but severe systemic toxicity. At the maximum tolerated doses, there is no meaningful antitumor activity when TNF-a is delivered systemically.…”

Selective enhancement of the tumour necrotic activity of TNF α with monoclonal antibody

“…In contrast to the effects of MAb 32 on TNF, activity in WEHI-164 cells, the antibody has been shown to be significantly more inhibitory than MAb 47 on the induction of procoagulant activity in cultured endothelial cells. The greater inhibitory potency of MAb 32 in the procoagulant assay, as compared with MAb 47 in receptor binding, is still unclear; however, it has been shown (Brett et al, 1989) that endothelial cells may have more than one class of TNF<,, receptor, of which the functionally representative one is reflected in the bioassay rather than in the radioreceptor assay (see below).…”

“…The recent identification of a natural TNFCt binding protein (Engelmann et al, 1989), which may have regulatory effects on the cytokine in vivo and the existence of at least two structurally distinct receptors (Hohman et al, 1989;Engelmann et al, 1989;Loetscher et al, 1990;Espevik et al, 1990), would also lend support to the above hypothesis. Endothelial cells appear to express two TNF receptors which mediate different biological effects of TNF (Brett et al, 1989). It appears that expression of tissue factor in response to TNF is signalled by a non-G protein linked receptor while increased vascular permeability in response to TNF occurs via a G protein-linked receptor.…”