The 12-Membered TNFR1 Peptide, as Well as the 16-Membered and 6-Membered TNF Peptides, Regulate TNFR1-Dependent Cytotoxic Activity of TNF.

Understanding the exact mechanisms of the activation of proinflammatory immune response receptors is very important for the targeted regulation of their functioning. In this work, we were able to identify the sites of the molecules in the proinflammatory cytokine TNF (tumor necrosis factor) and its TNFR1 (tumor necrosis factor receptor 1), which are necessary for the two-stage cytotoxic signal transduction required for tumor cell killing. A 12-membered TNFR1 peptide was identified and synthesized, interacting with the ligands of this receptor protein's TNF and Tag7 and blocking their binding to the receptor.

The Interaction of HMGB1 with the Proinflammatory TREM-1 Receptor Generates Cytotoxic Lymphocytes Active against HLA-Negative Tumor Cells.

High mobility group protein (HMGB1) is secreted by myeloid cells and cells of damaged tissues during inflammation, causing inflammatory reactions through various receptors, including TLR and RAGE. TREM-1 is considered to be one of the potential HMGB1 receptors. In this work, we have shown that the HMGB1 protein is able to bind to the TREM-1 receptor at high affinity both in solution and on the cell surface.

Short Peptides of Innate Immunity Protein Tag7 (PGLYRP1) Selectively Induce Inhibition or Activation of Tumor Cell Death via TNF Receptor.

In this study, we have found two peptides of Tag7 (PGLYRP1) protein-17.1A (HRDVQRT) and 17.1B (RSNYVLKG), that have different affinities to the TNFR1 receptor and the Hsp70 protein.

Short Peptides of Innate Immunity Protein Tag7 Inhibit the Production of Cytokines in CFA-Induced Arthritis.

The pathogenesis of autoimmune arthritis is a hot topic in current research. The main focus of this work was to study cytokines released in CFA-induced arthritis in ICR mice as well as the regulation of blood levels of cytokines by two peptides of the innate immunity protein Tag7 (PGLYRP1) capable of blocking the activation of the TNFR1 receptor. Arthritis was induced by local periarticular single-dose injections of 40 µL of complete Freund's adjuvant (CFA) into the left ankle joints of mice.

N-Terminal Peptide of PGLYRP1/Tag7 Is a Novel Ligand for TREM-1 Receptor.

An investigation of innate immunity receptors sheds light on the mechanisms of inflammation and associated immune reactions. One of the key immune regulators is the TREM-1 receptor, which is involved in both inflammation and antitumor immune response. In this article, we have obtained a new ligand for the TREM-1 receptor.

Protein PGLYRP1/Tag7 Peptides Decrease the Proinflammatory Response in Human Blood Cells and Mouse Model of Diffuse Alveolar Damage of Lung through Blockage of the TREM-1 and TNFR1 Receptors.

Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as "cytokine storm", which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation.

Hsp70 Interacts with the TREM-1 Receptor Expressed on Monocytes and Thereby Stimulates Generation of Cytotoxic Lymphocytes Active against MHC-Negative Tumor Cells.

The search for and analysis of new ligands for innate immunity receptors are of special significance for understanding the regulatory mechanisms of immune response. Here we show that the major heat shock protein 70 (Hsp70) can bind to and activate TREM-1, the innate immunity receptor expressed on monocytes. The Hsp70-TREM-1 interaction activates expression of TNFα and IFNγ mRNAs in monocytes and stimulates IL-2 secretion by PBMCs.

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

Search for novel regulatory protein fragments with potential functional roles is required both for understanding the immune response mechanisms and the development of targeted immunotherapy. Earlier we demonstrated that the PGLYRP1/Tag7 innate immunity protein can be regarded as an inhibitor of TNFα cytotoxic activity the interaction with its TNF receptor 1 (TNFR1). A C-terminal peptide fragment 17.

Cytokines TNFα, IFNγ and IL-2 Are Responsible for Signal Transmission from the Innate Immunity Protein Tag7 (PGLYRP1) to Cytotoxic Effector Lymphocytes.

Studies on the mechanisms of activation of cytotoxic lymphocyte subpopulations are an important research direction in modern immunology. This study provides a detailed analysis of the effect of Tag7 (PGRP-S, PGLYRP1) on the development of lymphocyte subpopulations cytotoxic against MHC-negative tumor cells in a pool of peripheral blood mononuclear cells (PBMCs). The results show that Tag7 can bind to the TREM-1 receptor on the surfaces of monocytes, thereby triggering the expression of mRNA TNFα and IFNγ.

Autoantibodies from SLE patients induce programmed cell death in murine fibroblast cells through interaction with TNFR1 receptor.

Various pathological processes are known to be associated with the production of IgG autoantibodies, which have high affinity for self-antigens and often cause tissue injury and the development of autoimmune diseases. However, the mechanism of their cytotoxic activity is not clearly understood yet. Here, we have shown that the action of these autoantibodies on cells expressing TNFR1 (the cell surface receptor for TNFα) can cause both caspase-dependent apoptosis and necroptosis of these cells, with suppression of apoptosis resulting in switching to RIP1-dependent necroptosis.

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

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.

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA-negative tumor cells.

Tilorone hydrochloride, a low-molecular-weight synthetic compound, induces interferon production and has been reported to have both antiviral and antitumor activities. Here, we have demonstrated the ability of tilorone to activate NK cells and specific subpopulations of cytotoxic CD4+ and CD8+ T lymphocytes that recognize immune-evasive tumor cells and kill them via the FasL-Fas interaction. We have also performed a comparative analysis of characteristics between lymphocytes activated in the fraction of human peripheral blood mononuclear cells (PBMCs) upon treatment with different stimulants of the immune response: tilorone, innate immunity protein Tag7, and cytokine IL-2, a regulator of adaptive immunity.

FasL on the surface of Tag7 (PGRP-S)-activated lymphocytes induces necroptosis in HLA-negative tumor cells with the involvement of lysosomes and mitochondria.

Recently we have found that cytokine IL-2 and innate immunity protein Tag7 activate cytotoxic lymphocytes that kill HLA-negative tumor cells, inducing both apoptosis and necroptosis. Here we decrypt the processes, taking part in necroptosis execution after FasL-Fas interaction. Necroptosis begins with RIPK1 activation and necrosome formation.

Innate immunity protein Tag7 (PGRP-S) activates lymphocytes capable of Fasl-Fas-dependent contact killing of virus-infected cells.

The innate immunity protein Tag7 (PGRP-S, PGLYRP1) is involved in antimicrobial and antitumor defense. As shown in our previous studies, Tag7 specifically interacts with the major heat shock protein Hsp70 to form a stable Tag7-Hsp70 complex with cytotoxic activity against tumor cells. A stable complex of Tag7 with the calcium-binding protein Mts1 (S100A4) stimulates migration of lymphocytes.

Innate Immunity Protein Tag7 Induces 3 Distinct Populations of Cytotoxic Cells That Use Different Mechanisms to Exhibit Their Antitumor Activity on Human Leukocyte Antigen-Deficient Cancer Cells.

The search for new immune response mechanisms capable of controlling immune-evasive tumor cells devoid of the MHC antigen is a challenging task for immunologists. In this study, we found that the treatment of human peripheral blood lymphocytes with the innate immunity protein Tag7 (PGRP-S, PGLYRP1) induces differentiation of the populations of NK (natural killer) cells and CD8+ and CD4+ T lymphocytes that are cytotoxic for human leukocyte antigen-negative tumor cells. These populations employ different mechanisms of tumor cell lysis (based on the release of granzymes in the case of NK cells and on the FasL-Fas interaction in the case of CD8+ and CD4+ T lymphocytes) and induce different death pathways (apoptosis or necroptosis) in tumor cells.

CD3 CD8 NKG2D T Lymphocytes Induce Apoptosis and Necroptosis in HLA-Negative Cells via FasL-Fas Interaction.

An important problem in cellular immunology is to identify new populations of cytotoxic lymphocytes capable of killing tumor cells that have lost classical components of MHC-machinery and to understand mechanisms of the death of these cells. We have previously found that CD4 CD25 lymphocytes appear in the lymphokine-activated killer (LAK) cell culture, which carry Tag7 (PGRP-S) and FasL proteins on their surface and can kill Hsp70- and Fas-expressing HLA-negative cells. In this work, we have continued to study the mechanisms of killing of the HLA-negative tumor cells, focusing this time on the CD8 lymphocytes.

FasL and the NKG2D receptor are required for the secretion of the Tag7/PGRP-S-Hsp70 complex by the cytotoxic CD8 lymphocytes.

Tag7 (PGRP-S or PGLYRP1), while possessing an antimicrobial activity, also exhibits an antitumor effect when in complex with the major heat shock protein Hsp70. The cytotoxic Tag7-Hsp70 complex is secreted by lymphocytes after interaction with the HLA-negative tumors. Previously, we have shown that IL-2 induces formation of the CD4 and CD8 cytotoxic subpopulations of human lymphocytes, which kill tumor cells through the FasL-Fas interaction.

The Tag7-Hsp70 cytotoxic complex induces tumor cell necroptosis via permeabilisation of lysosomes and mitochondria.

Tag7 (PGRP-S, or PGLYRP1), an innate immunity protein, plays an important role in the immune defense system. It forms a stable cytotoxic complex with the heat shock protein Hsp70. This complex can induce an apoptotic or necroptotic tumor cell death by interacting with the TNFR1 receptor.

Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor.

Tag7 (also known as peptidoglycan recognition protein PGRP-S, PGLYRP1), an innate immunity protein, interacts with Hsp70 to form a stable Tag7-Hsp70 complex with cytotoxic activity against some tumor cell lines. In this study, we have analyzed the programmed cell death mechanisms that are induced when cells interact with the Tag7-Hsp70 complex, which was previously shown to be released by human lymphocytes and is cytotoxic to cancer cells. We show that this complex induces both apoptotic and necroptotic processes in the cells.

Liposome-encapsulated peptides protect against experimental allergic encephalitis.

Multiple sclerosis (MS) is a severe inflammatory and neurodegenerative disease with an autoimmune background. Despite the variety of therapeutics available against MS, the development of novel approaches to its treatment is of high importance in modern pharmaceutics. In this study, experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats has been treated with immunodominant peptides of the myelin basic protein (MBP) encapsulated in mannosylated small unilamellar vesicles.

Extracellular HspBP1 inhibits formation of a cytotoxic Tag7-Hsp70 complex in vitro and in human serum.

Tag7 (PGRP-S) was described as an innate immunity protein. Earlier we have shown that Tag7 forms with Hsp70 a stable complex with cytotoxic and antitumor activity. The same complex is formed in and secreted by cytotoxic T-lymphocytes.

Design of targeted B cell killing agents.

B cells play an important role in the pathogenesis of both systemic and organ-specific autoimmune diseases. Autoreactive B cells not only produce autoantibodies, but also are capable to efficiently present specific autoantigens to T cells. Furthermore, B cells can secrete proinflammatory cytokines and amplify the vicious process of self-destruction.

The heat shock-binding protein (HspBP1) protects cells against the cytotoxic action of the Tag7-Hsp70 complex.

Heat shock-binding protein HspBP1 is a member of the Hsp70 co-chaperone family. The interaction between HspBP1 and the ATPase domain of the major heat shock protein Hsp70 up-regulates nucleotide exchange and reduces the affinity between Hsp70 and the peptide in its peptide-binding site. Previously we have shown that Tag7 (also known as peptidoglycan recognition protein PGRP-S), an innate immunity protein, interacts with Hsp70 to form a stable Tag7-Hsp70 complex with cytotoxic activity against some tumor cell lines.

Unexpected deeds of familiar proteins: Interplay of Hsp70, PGRP-S/Tag7 and S100A4/Mts1 in host vs. cancer combat.

We consider the novel means of attack and defense in the host versus cancer combat that involve interactions between widespread multifunctional proteins, focusing on the aspects that may seem paradoxical in the framework of established notions. Particularly, we show that a protein broadly known for its protective functions such as Hsp70 can make a tumoricidal "binary weapon" with another nontoxic protein Tag7 (PGRP-S); that the same Hsp70, a ubiquitous intracellular chaperone, when expressed on the MHC-negative tumor cell surface, can itself be the hallmark of immune evasion rather than a primordial MHC substitute; that a device functionally equivalent to the T-cell receptor (Tag7-Centered Recognizer) can be assembled of components in no way related to the classical pathways of T-cell-mediated immunity, and operate where the orthodox immunosurveillance fails; and that one and the same protein Mts1 (S100A4) under different circumstances may work as "reactive armor" of a tumor cell against humoral agents and as a vital part of the T-cell machinery aimed against immunoevasive cells, i.e.