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

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.

Macrophage p38α promotes nutritional steatohepatitis through M1 polarization

“…TNF-a can activate p38a after binding with TNF-a receptor-associated factor 2. 27 TNF-a is also known to mediate the alteration of M1/M2 macrophage polarization. 28 CXCL10 contributes to p38 activation when bound to its receptor CXCR3 29 and mediates hepatic macrophage M1 polarization.…”

TNF receptor signalling in autoinflammatory diseases

“…MTX is an immunosuppressive agent which was initially used to improve clinical outcomes of patients with IBS and CD who had developed anti-drug antibodies (ADA) when administered anti-TNF biologics (infliximab, adalimumab or golimumab) (105,106). Interestingly, the TNFR peptide does not prevent the binding of TNF to TNFR1 and other signalling molecules it normally activates, but, instead, selectively inhibits p38 MAPK activation and function (115). By improving drug targeting, in this way, the rate of potential side-effects of other anti-TNF biologics will decrease, but specificity will increase and this will also serve as a valuable tool for elucidating mechanisms of disease pathogenesis in vivo.…”

Extracorporeal shock wave therapy decreases COX‐2 by inhibiting TLR4‐NFκB pathway in a prostatitis rat model

“…TRAF2 was considered to be associated with the generation of an inflammatory response . In this study, we wanted to find if ESWT will activate the TRAF2.…”

“…TRAF2 was considered to be associated with the generation of an inflammatory response. 19 In this study, we wanted to find if ESWT will activate the TRAF2. The results of Western blot analysis ( Figure 3A and 3B) showed after ESWT more phosphorylated TRAF2 (p-TRAF2) existed in the prostate, which meant ESWT phosphorylated the TRAF2 in rats.…”