Reverse Signaling Contributes to Control of Chronic Inflammation by Anti-TNF Therapeutics

Anti-tumor necrosis factor (TNF) monoclonal antibodies and TNF receptor ectodomain fusion protein are in clinical use to neutralize circulating TNF and ameliorate symptoms of many autoimmune diseases and pathological conditions with chronic inflammation. In this paper we present data to prove that reverse signaling, elicited by agonist molecules interacting with the membrane-bound TNF of myeloid cells, significantly contributes to the therapeutic effect of these anti-TNF medicines. Interaction of agonist monoclonals with cell surface TNF significantly attenuates the expression of pro-inflammatory cytokines and induces changes in the production of extracellular and intracellular signaling molecules. This phenomenon is not dependent on the Fc portion of antibodies as Fab constructs are as efficient as full antibody molecules.

• Publication year

  2015

• Venue

  Antibodies

• Publication date

  2015-06-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3390/ANTIB4020123
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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  2008cited by this paper
• The cytokine and chemokine network in psoriasis.

  2007cited by this paper
• Pathogen recognition and innate immunity.

  2006influential reference
• Adenovirus Infection Dramatically Augments Lipopolysaccharide-Induced TNF Production and Sensitizes to Lethal Shock1

  2005cited by this paper
• Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha.

  2005influential reference
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  2004influential reference
• Toll-like receptor signalling

  2004cited by this paper
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  2004cited by this paper
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  2001cited by this paper
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  2001cited by this paper
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  2001influential reference
• Outside-to-Inside Signal Through the Membrane TNF-α Induces E-Selectin (CD62E) Expression on Activated Human CD4+ T Cells1

  2001cited by this paper
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  2001cited by this paper
• Reverse Signaling Through Transmembrane TNF Confers Resistance to Lipopolysaccharide in Human Monocytes and Macrophages1

  2000cited by this paper
• A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling.

  2000influential reference
• Off-Label Use of Haemophilus Vaccine in Combination With DTaP Vaccine

  1998cited by this paper
• Construction and initial characterization of a mouse-human chimeric anti-TNF antibody.

  1993cited by this paper
• Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.

  1993cited by this paper
• Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

  1991cited by this paper
• Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.

  1990cited by this paper
• Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones

  1989cited by this paper
• Interleukin 6, the third mediator of acute‐phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 β and tumor necrosis factor‐α

  1988cited by this paper
• Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis factor-alpha.

  1988cited by this paper

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  2020cites this paper
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