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 language | English |
|---|---|
| Article number | 1365 |
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | Nature Communications |
| Volume | 9 |
| DOIs | |
| Publication status | Published - 1 Dec 2018 |
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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 journal › Article
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
VL - 9
SP - 1
EP - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1365
ER -