Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29636466.
- Also identified by DOI 10.1038/s41467-018-03640-y and PMC identifier 5893557.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF<sub>70-80</sub>, is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF<sub>70-80</sub> 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 TNF<sub>70-80</sub>. Peptides with this TNFRI sequence, such as TNFRI<sub>206-211</sub> 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. TNFRI<sub>206-211</sub> does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI<sub>206-211</sub> 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.
Medical subject headings
- Anti-Inflammatory Agents
- Arthritis, Experimental
- Peptide Fragments
- Peritonitis
- Pneumonia
- Pneumonia, Viral
- p38 Mitogen-Activated Protein Kinases