TY - JOUR
T1 - Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation
AU - Mukaro, Violet R.
AU - Quach, Alex
AU - Gahan, Michelle E.
AU - Boog, Bernadette
AU - Huang, Zhi H.
AU - Gao, Xiuhui
AU - Haddad, Carol
AU - Mahalingam, Suresh
AU - Hii, Charles S.
AU - Ferrante, Antonio
N1 - Funding Information:
We thank Dr. George Mayne, Hannah Sundqvist and Bao Duy Ngo for assistance with aspects of the intracellular signalling studies and Dr. Simon Schmidt for assistance with the generation of the receptor mutants. We are indebted to Professor David Hume, Roslin Institute, University of Edinburgh, Professor Steven Krilis, University of Sydney and Prof Matthew Sweet, University of Queensland for invaluable advice and on the research and manuscript. V.R.M. was supported by an International Postgraduate Scholarship of the University of Adelaide, Z.H.H. by an MS Mcleod Fellowship, Women's and Children's Hospital Foundation and S.M. by an ARC Future Fellowship. The work received financial support from the National Health and Medical Research Council of Australia, University of Adelaide Research Grants, and Women's and Children's Hospital Foundation, North Adelaide, South Australia.
Funding Information:
We thank Dr. George Mayne, Hannah Sundqvist and Bao Duy Ngo for assistance with aspects of the intracellular signalling studies and Dr. Simon Schmidt for assistance with the generation of the receptor mutants. We are indebted to Professor David Hume, Roslin Institute, University of Edinburgh, Professor Steven Krilis, University of Sydney and Prof Matthew Sweet, University of Queensland for invaluable advice and on the research and manuscript. V.R.M. was supported by an International Postgraduate Scholarship of the University of Adelaide, Z.H.H. by an MS Mcleod Fellowship, Women’s and Children’s Hospital Foundation and S.M. by an ARC Future Fellowship. The work received financial support from the National Health and Medical Research Council of Australia, University of Adelaide Research Grants, and Women’s and Children’s Hospital Foundation, North Adelaide, South Australia.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 -
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.
AB -
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.
KW - tumor necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=85045314527&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03640-y
DO - 10.1038/s41467-018-03640-y
M3 - Article
C2 - 29636466
AN - SCOPUS:85045314527
VL - 9
SP - 1
EP - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1365
ER -