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
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 -