Interaction between Transmembrane TNF and TNFR1/2 Mediates the Activation of Monocytes by Contact with T Cells

Abstract

Monocytes and monocytic cells produce proinflammatory cytokines upon direct cell contact with activated T cells. In the autoimmune disease rheumatoid arthritis, the pivotal role of TNF-α implies that the interaction between transmembrane TNF-α (mTNF) and the TNF receptors (TNFR1 and TNFR2) might participate in the T cell contact-dependent activation of monocytes. Accordingly, treatment of rheumatoid arthritis by administration of a TNF-α-blocking Ab was found to significantly decrease TNF-α production by monocytes. Several lines of evidence indicated that signaling through TNFR1/2 and through mTNF (reverse signaling) is involved in TNF-α production by monocytes after T cell contact: 1) blocking mTNF on activated T cells leads to a significant reduction in TNF-α production; 2) down-regulation of TNFR1/2 on monocytes by transfection with small interfering RNA results in diminished TNF-α production; 3) blocking or down-regulating TNFR2 on activated T cells inhibits TNF-α production, indicating that mTNF on the monocyte surface mediates signaling; 4) ligation of mTNF on monocytes by surface TNFR2 transfected into resting T cells induces TNF-α production due to reverse signaling by mTNF; and 5) ligation of mTNF on monocytes by a soluble TNFR2:Ig receptor construct induces TNF-α production due to reverse signaling. In conclusion, we identified mTNF and TNFR1/2 as interaction partners contributing to TNF-α production in monocytes. Both pathways initiated by mTNF-TNFR interaction are likely to be inhibited by treatment with anti-TNF-α Abs.

Transmembrane TNF-α Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-β: Therapeutic Implications

“…ficient mTNF-a signaling, and we found that the signaling pathway led to the production of TGF-b. Induction of TGF-b production, however, is not a universal response of cells to mTNF-a signaling, because monocytes were shown to produce TNF-a and not TGF-b when their mTNF-a was triggered by the TNFRs of activated T cells (43). We have also identified the signaling pathway that regulates mTNF-a-induced TGF-b production in macrophages.…”

Abnormal Expression of Long Noncoding RNAs in Primary Immune Thrombocytopenia: A Microarray Related Study

“…In general, signaling via TNF-TNFR1 involves the MAPK and NF-κβ pathways. In contrast, signaling via TNF-TNFR2 is limited to CD4 + T cells, CD8 + T cells, and endothelial cells, and signaling via NF-κβ can be stimulated as well [70][71][72][73][74]. Between the P2 and N group data, the most enriched pathway that was identified was the, "NF-kappa B signaling pathway -Homo sapiens (human)" (see online suppl.…”

“…S2a). Previous studies have shown that TNFR1 and TNFR2 are two important receptors that mediate signaling downstream of TNF activation and binding [70]. In general, signaling via TNF-TNFR1 involves the MAPK and NF-κβ pathways.…”

Les anticorps : mieux les connaître pour mieux s’en servir

“…Cependant, certains individus traités par anti-TNFα présentent une vulnérabilité aux infections, en particulier à la tuberculose (➜). Cet effet secondaire a été expliqué par l'existence de TNFα membranaire (mTNFα) à la surface de lymphocytes T qui est responsable de l'activation des monocytes producteurs de TNFα soluble (sTNFα) par les lymphocytes T. Son blocage par les Acm anti-TNFα conduit à une diminution importante de la production de sTNFα [38] qui est un facteur de survie des lymphocytes T effecteurs/mémoires impliqués dans la défense anti-tuberculose [39]. Les Acm anti-TNFα agiraient donc en inhibant la survie des lymphocytes T effecteurs/mémoires spécifiques induite par le sTNFα, favorisant une réactivation de l'infection latente.…”