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

• DOI: 10.1038/s41467-018-03640-y
• Publication Date: 2018-04-04T15:06:07Z
• 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
• Keywords: Lipopolysaccharides; bacteria (microorganisms); Neutrophils; respiratory syncytial virus; Science; Immunology; Pneumonia, Viral; mus; Anti-Inflammatory Agents; 610; Peritonitis; Article; Receptors, Tumor Necrosis Factor; Mice; 03 medical and health sciences; tumour-necrosis factors; 616; Animals; Humans; Clinical microbiology; Respiratory Burst; Mice, Inbred BALB C; 0303 health sciences; Q; Oncology and carcinogenesis; Pneumonia; Arthritis, Experimental; Peptide Fragments; Respiratory Syncytial Viruses; 3. Good health; Disease Models, Animal; Gene Expression Regulation; Platelet Glycoprotein GPIb-IX Complex; Female; Protein Binding

AbstractDespite 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 TNF70–80binds 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 TNFRI206–211bind 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. TNFRI206–211does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI206–211inhibits 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.