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.

Details

Title
Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation
Author
Mukaro, Violet R 1 ; Quach, Alex 2 ; Gahan, Michelle E 3 ; Boog, Bernadette 2 ; Huang, Zhi H 4 ; Gao, Xiuhui 2 ; Haddad, Carol 5 ; Mahalingam, Suresh 6   VIAFID ORCID Logo  ; Hii, Charles S 2 ; Ferrante, Antonio 7 

1  Department of Immunopathology, SA Pathology, Women’s and Children’s Hospital, North Adelaide, SA, Australia; Discipline of Paediatrics, School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Andrew Love Cancer Center, Geelong Hospital, School of Medicine, Deakin University, Geelong, VIC, Australia 
2  Department of Immunopathology, SA Pathology, Women’s and Children’s Hospital, North Adelaide, SA, Australia; Discipline of Paediatrics, School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia 
3  Faculty of Science and Technology, University of Canberra, Bruce, ACT, Australia 
4  Department of Immunopathology, SA Pathology, Women’s and Children’s Hospital, North Adelaide, SA, Australia; Discipline of Paediatrics, School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; College of Medicine, University of Illinois, Chicago, IL, USA 
5  Department of Immunopathology, SA Pathology, Women’s and Children’s Hospital, North Adelaide, SA, Australia; Discipline of Paediatrics, School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, SA, Australia 
6  Emerging Viruses and Inflammation Research Group, Institute of Glycomics, Griffith University, Gold Coast, QLD, Australia 
7  Department of Immunopathology, SA Pathology, Women’s and Children’s Hospital, North Adelaide, SA, Australia; Discipline of Paediatrics, School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia 
Pages
1-13
Publication year
2018
Publication date
Apr 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-03640-y
ProQuest document ID
2023717226
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.