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

Violet R. Mukaro, Alex Quach, Michelle E. Gahan, Bernadette Boog, Zhi H. Huang, Xiuhui Gao, Carol Haddad, Suresh Mahalingam, Charles S. Hii, Antonio Ferrante

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 70-80 , is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF 70-80 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 TNF 70-80 . Peptides with this TNFRI sequence, such as TNFRI 206-211 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. TNFRI 206-211 does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI 206-211 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.

Original languageEnglish
Article number1365
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 1 Dec 2018

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necrosis
Tumor Necrosis Factor Receptors
Biological Products
tumors
Respiratory Burst
Tumor Necrosis Factor-alpha
Inflammation
peptides
bursts
TNF Receptor-Associated Factor 2
Chemical activation
activation
neutrophils
N-Formylmethionine Leucyl-Phenylalanine
arthritis
Peptides
Cytokine Receptors
Respiratory Syncytial Viruses
Carrageenan
viruses

Cite this

Mukaro, Violet R. ; Quach, Alex ; Gahan, Michelle E. ; Boog, Bernadette ; Huang, Zhi H. ; Gao, Xiuhui ; Haddad, Carol ; Mahalingam, Suresh ; Hii, Charles S. ; Ferrante, Antonio. / Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation. In: Nature Communications. 2018 ; Vol. 9. pp. 1-13.
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Mukaro, VR, Quach, A, Gahan, ME, Boog, B, Huang, ZH, Gao, X, Haddad, C, Mahalingam, S, Hii, CS & Ferrante, A 2018, 'Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation', Nature Communications, vol. 9, 1365, pp. 1-13. https://doi.org/10.1038/s41467-018-03640-y

Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation. / Mukaro, Violet R.; Quach, Alex; Gahan, Michelle E.; Boog, Bernadette; Huang, Zhi H.; Gao, Xiuhui; Haddad, Carol; Mahalingam, Suresh; Hii, Charles S.; Ferrante, Antonio.

In: Nature Communications, Vol. 9, 1365, 01.12.2018, p. 1-13.

Research output: Contribution to journalArticle

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