Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation.

Abstract

Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF70-80, is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF70-80 binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF70-80. Peptides with this TNFRI sequence, such as TNFRI206-211 bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI206-211 does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI206-211 inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.

• Authors: Violet R Mukaro, Alex Quach, Michelle E Gahan, Bernadette Boog, Zhi H Huang, Xiuhui Gao, Carol Haddad, Suresh Mahalingam, Charles S Hii, Antonio Ferrante
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 1365 (04 10 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29636466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Lipopolysaccharides
• Peptide Fragments
• Platelet Glycoprotein GPIb-IX Complex
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• adhesion receptor
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Anti-Inflammatory Agents (chemistry, metabolism, pharmacology)
• Arthritis, Experimental (drug therapy, genetics, immunology, pathology)
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Humans
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Mice
• Mice, Inbred BALB C
• Neutrophils (cytology, drug effects, immunology)
• Peptide Fragments (biosynthesis, genetics, pharmacology)
• Peritonitis (drug therapy, genetics, immunology, pathology)
• Platelet Glycoprotein GPIb-IX Complex (genetics, immunology)
• Pneumonia (drug therapy, genetics, immunology, pathology)
• Pneumonia, Viral (drug therapy, genetics, immunology, pathology)
• Protein Binding
• Receptors, Tumor Necrosis Factor (antagonists & inhibitors, genetics, immunology)
• Respiratory Burst (drug effects)
• Respiratory Syncytial Viruses (immunology, pathogenicity)
• Signal Transduction
• Tumor Necrosis Factor-alpha (genetics, immunology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, immunology)