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.
Highlights
Cytokines play a crucial role in the development of the immune system, eliciting immune responses, and often preventing autoimmune reactions [1]
Three significant observations were made in this study: (1) the 12-membered peptide 17.1 can be regarded as a novel inhibitor of TNFα; (2) peptide 17.1 forms a cytotoxic complex with heat shock protein Hsp70; and (3) peptide 17.1 can exhibit an anti-inflammatory effect in laboratory mice with
We demonstrated that Tag7 protein binds to TNFR1 and can have two opposite functions during cytolysis of tumor cells [15]
Summary
Cytokines play a crucial role in the development of the immune system, eliciting immune responses, and often preventing autoimmune reactions [1]. TNF (tumor necrosis factor) is one of the oldest known cytokines, that plays an important role in the mechanisms of inflammation and programmed cell death [2,3] TNF contributes to inflammatory processes by enhancing expression of the cell adhesion molecules. TNF can induce proliferation of the immune cells via activation of the NFκB transcription factor [4,5,6], playing an important role in immune defenses against different diseases [7]. A signal for induction of the NFκB transcription factor, leading to activation of immune cells, is generated in some cases, while
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