The lectin-like domain of tumor necrosis factor-α increases membrane conductance in microvascular endothelial cells and peritoneal macrophages

Abstract

Herein, we show that TNF exerts a pH‐dependent increase in membrane conductance in primary lung microvascular endothelial cells and peritoneal macrophages. This effect was TNF receptor‐independent, since it also occurred in cells isolated from mice deficient in both types of TNF receptors. A TNF mutant in which the three amino acids critical for the lectin‐like activity were replaced by an alanine did not show any significant effect on membrane conductance. Moreover, a synthetic 17‐amino acid peptide of TNF, which was previously shown to exert lectin‐like activity, also increased the ion permeability in these cells. The amiloride sensitivity of the observed activity suggests a binding of TNF to an endogenousion channel rather than channel formation by TNF itself. This may have important implications in mechanisms of TNF‐mediated vascular pathology.

Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital

“…The activity of amiloride-sensitive non-selective cation channels, which is highly regulated, is inhibited by amiloride and activated by inflammatory mediators such as LPS, TNFa and PGE2 [34][35][36]. Such an activation may allow NH 4 þ to enter the brain [26] which will cause a decrease in intracellular pH.…”

On the existence of cytokines in invertebrates

“…Moreover, preincubating VSG with TNF impairs the activation of the proPO cascade, confirming that the interaction with a N,N ¢-diacetylchitobiose carbohydrate moiety on VSG lies at the basis of CCF and TNF trypanolytic activity. As mentioned above, TNF increases the membrane conductance in mammalian cells, interacting with ion-channels or ion-channel-coupled molecules through its TIP N,N ¢-diacetylchitobiose lectin-like domain [140,141]. Similarly, when murine endothelial cells or macrophages were activated with CCF, an increase in membrane .…”

“…Recent evidence suggests that cytokines may also contribute to inflammatory reactions in vertebrates through their lectin-like activity. In this regard, TNF was reported to increase the membrane conductance in endothelial cells and peritoneal macrophages [140,141]. This effect is independent of the TNF receptor since it also occurs in cells isolated from mice deficient in both types of TNF receptors.…”

“…This effect is independent of the TNF receptor since it also occurs in cells isolated from mice deficient in both types of TNF receptors. In contrast, the ion-channel-gating activity of TNF is mediated by the N,N ¢-diacetylchitobiose lectinlike domain of molecule (the TIP domain) located at the tip of the trimeric TNF molecule and spatially distinct from the TNF-receptor binding site [127,131,140,141].…”

The Tumor Necrosis Factor-Derived TIP Peptide: A Potential Anti-Edema Drug

“…2. Subsequently, the lectin-like domain of TNF (green triangle in the TNF trimer) was found to activate sodium uptake in mammalian cells and in flooded rat and mouse lungs [29, 31,32,41], whereas the TNF receptor binding sites (red ellips in the TNF trimer) rather inhibit sodium uptake, e.g. by downregulating ENaC expression in type II alveolar epithelial cells [24,25].…”