Reverse Signaling Through Transmembrane TNF Confers Resistance to Lipopolysaccharide in Human Monocytes and Macrophages

Abstract

We have previously reported that the CD14+ monocytic subpopulation of human PBMC induces programmed cell death (apoptosis) in cocultured endothelial cells (EC) when stimulated by bacterial endotoxin (LPS). Apoptosis is mediated by two routes, first via transmembrane TNF-α (mTNF) expressed on PBMC and, in addition, by TNF-independent soluble factors that trigger apoptosis in EC. Neutralizing anti-TNF mAb completely blocked coculture-mediated apoptosis, despite the fact that there should have been additional soluble cell death factors. This led to the hypothesis that a reverse signal is transmitted from the TNF receptor on EC to monocytes (MO) via mTNF that prevents the production of soluble apoptotic factors. Here we have tested this hypothesis. The results support the idea of a bidirectional cross-talk between MO and EC. Peripheral blood MO, MO-derived macrophages (MΦ), or the monocytic cell line Mono Mac 6 were preincubated with human microvascular EC that constitutively express TNF receptor type I (TNF-R1) and subsequently stimulated with LPS. Cell-free supernatants of these preparations no longer induced EC apoptosis. The preincubation of MO/MΦ with TNF-reactive agents, such as mAb and soluble receptors, also blocked the production of death factors, providing further evidence for reverse signaling via mTNF. Finally, we show that reverse signaling through mTNF mediated LPS resistance in MO/MΦ as indicated by the down-regulation of LPS-induced soluble TNF and IL-6 as well as IL-1 and IL-10.

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

“…5D). Another remote possibility that we considered is that reverse signaling through mTNF might be elicited by either sTNFR1-or TNF-neutralizing antibodies (23,34,49). To mitigate these potential confounding effects, we developed a procedure utilizing siRNA for efficient down-regulation of TNF in vivo (5) as a highly specific alternative approach for demonstrating TNF-mediated protection in HSV-1-infected p55 Ϫ/Ϫ p75 Ϫ/Ϫ mice.…”

Enhanced Secretion of IFN-γ by Activated Th1 Cells Occurs Via Reverse Signaling Through TNF-Related Activation-Induced Cytokine

“…This raised the possibility that the soluble receptors of TNFR superfamily might be able to transduce signals by cross-linking their ligands expressed on cell surface, and cannot be only regarded as decoy receptor to inhibit the interaction between membrane form ligand and receptor. Recently, Eissner et al (38) demonstrated that reverse signaling through transmembrane TNF conferred resistance to LPS in human monocytes and macrophages by down-regulation of LPS-induced soluble TNF and IL-6 as well as IL-1 and IL-10. Based on this information, the shedding of TNFR during inflammation (39) might have the potential to bind to the membrane form TNF to down-regulate inflammation reaction.…”

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

“…[36][37][38][39] This means, in addition to the welldefined signaling cascades transduced by TNFR superfamily, members of the TNF superfamily can transduce reverse signal after engagement with their receptors. Our previous reports on RANK and DcR3 have indicated additional players by these soluble receptors in the regulation of cell function, and confirmed the concept of reverse signaling.…”

“…29,[36][37][38][39] Since our recent study suggested that DcR3, like other members of the TNFR superfamily, is capable of triggering 'reverse signaling' to modulate monocyte differentiation, [33][34][35] we are interested in this study to understand whether DcR3 has any effects in modulating osteoclastogenesis from monocytes/macrophages.…”