A 12-mer Peptide of Tag7 (PGLYRP1) Forms a Cytotoxic Complex with Hsp70 and Inhibits TNF-Alpha Induced Cell Death

Abstract

Investigation of interactions between a pro-inflammatory cytokine tumor necrosis factor (TNFα) and its receptor is required for the development of new treatments for autoimmune diseases associated with the adverse effects of TNFα. Earlier, we demonstrated that the innate immunity protein Tag7 (PGRP-S, PGLYRP1) can interact with the TNFα receptor, TNFR1, and block the transduction of apoptotic signals through this receptor. A complex formed between the Tag7 protein and the major heat shock protein Hsp70 can activate TNFR1 receptor and induce tumor cell death via either apoptotic or necroptotic pathway. In this study, we show that a 12-mer peptide, designated 17.1, which was derived from the Tag7 protein, can be regarded as a novel TNFα inhibitor, also is able to form a cytotoxic complex with the heat shock protein Hsp70. This finding demonstrates a new role for Hsp70 protein in the immune response. Also, this new inhibitory 17.1 peptide demonstrates an anti-inflammatory activity in the complete Freund’s adjuvant (CFA)-induced autoimmune arthritis model in laboratory mice. It appears that the 17.1 peptide could potentially be used as an anti-inflammatory agent.

A 8-mer Peptide of PGLYRP1/Tag7 Innate Immunity Protein Binds to TNFR1 Receptor and Inhibits TNFα-Induced Cytotoxic Effect and Inflammation

“…The inhibition of cytotoxic activity of TNFa, the Tag7-Hsp70 complex and autoimmune antibodies with anti-TNFR1 antibodies matches our earlier findings showing that all the three investigated inducers cause TNFR1-mediated cell death (13).…”

“…Once the inhibition of the TNFa cytotoxic activity by peptide 17.1 had been elucidated, the effect of this peptide on generalized inflammatory processes, including those induced by this cytokine, was studied. Protective activity of peptide 17.1 in the model of CFA-induced arthritis was described earlier (13).…”

“…We believe that the specificity of the inhibition of the cytotoxic activity of TNF under the action of peptide 17.1A consists in its competition with TNF for binding to TNFR1 on the cell surface. In previous studies, we have shown that TNF displaces peptide 17.1 from the complex with TNFR1 (13). This mechanism is the key difference between used nowadays therapeutic agents such as Infliximab and proposed in these work agents.…”

Mechanisms of Action of the PGLYRP1/Tag7 Protein in Innate and Acquired Immunity

“…С помощью ограниченного трипсинолиза выделен 12-членный пептид, расположенный на С-концевом участке Tag7. Этот пептид способен связываться с рецептором TNFR1 в растворе и на клеточной поверхности [41] [41]. Интересно, что этот же пептид способен взаимодействовать с белком теплового шока Hsp70 и образовывать цитотоксический комплекс 17.1-Hsp70, индуцирующий смерть клеток [41].…”

“…Противовоспалительное действие пептида 17.1 изучали на модели аутоиммунного артрита, индуцированного ПАФ (полный адъювант Фрейнда), который стимулирует выделение TNF-α в ткани. Установлено протективное действие этого пептида на хрящевую и костную ткань голеностопного сустава мышей [41]. Можно предположить, что пептид 17.1 окажется перспективным лекарственным соединением, способным блокировать развитие воспалительных процессов.…”