Proinflammatory Function For Grp94

GRP94 was reported to be a pro-inflammatory molecule following the demonstration of TNF-a release, along with other pro-inflammatory cytokines, from macrophages upon exposure to GRP94 (Basu et al., 2000). To date, NF-kB signaling and NO release have also been attributed to stimulation with GRP94, as well as dendritic cell maturation (Panjwani et al., 2002). Signaling pathways implicated include the MAPK, ERK, and JNK pathways (Vabulas et al., 2002). All have been described to be upstream of...

The Mechanistic Basis To The Antiinflammatory Properties Of Stress Proteins

The precise mechanism underlying the anti-inflammatory properties of high-dose gp96 is currently uncertain, however there are a number of different stages in the development of an immune response at which gp96 might influence the qualitative nature of that response. Firstly, it might influence the phenotype (antigen expression, cytokine secretion profile) of APCs, particularly DCs, and their capacity to activate and influence the functional phenotype of responding T cell populations. Secondly,...

Uptake of HSPS into Cells

Although most studies of extracellular HSP focus on their roles in the immune response, it is also important to remember that HSP were first identified as protective chaperones. Extracellular HSP may be important in the protection of cells, especially those cells that produce low levels of HSP. HSP can bind to cell surfaces and enter cells (Becker et al., 2002 Guzhova et al., 2001 Guzhova et al., 1998). Glial cells release Hsp72, and this release is increased in response to heat shock (Guzhova...

Hsps As Biomarkers

Many studies are showing serum HSP levels to be affected by several disease processes, leading to the suggestion that they may be useful clinical markers (Hunter-Lavin et al., 2004b Oglesbee et al., 2005 Pockley, 2003 Wright et al., 2000b Xu et al., 2000b). As well as being simply elevated in patients compared to controls, they are also affected by the extent of disease and complications in some patients (Hunter-Lavin et al., 2004b Oglesbee et al., 2005). Lowering physiological stress by...

The Pro And Antiinflammatory Properties Of The Stress Protein Gp96

GRAHAM POCKLEY* AND MUNITTA MUTHANA Immunobiology Research Unit, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, U.K. Abstract Although the stress protein gp96 is commonly perceived as being a universal activator of antigen presenting cells and an inducer of tumour-specific immunity, at high doses it can inhibit the induction of tumour-specific immunity and experimental autoimmune disease by a mechanism which appears to involve immunoregulatory CD4+ T cells....

Evidence That Exosomes Play A Role In Stressinduced Hsp72 Release

In our laboratory, we sought to determine whether heat shock at physio-logical pathophysiological temperatures, i.e. during febrile states, stimulated the release of HSPs, and whether stress-induced HSP72 release displayed cell specificity. Initially, we confirmed that stress-induced HSP72 release occurred independently of the classical secretory pathway (based on the inability of Brefeldin A treatment to inhibit stress-induced HSP72 release), and that non-specific processes such as cell lysis...

The Origin And Cellular Functions Of Grp94

GRP94, glucose-regulated protein 94, was first identified as a protein up-regulated during glucose deprivation and has subsequently been rediscovered multiple times (endoplasmin, tumor rejection antigen 1 (TRA1), glycoprotein 96 (gp96)) (Koch et al., 1985 Lewis et al., 1985 Shiu et al., 1977 Srivastava et al., 1986). For simplicities sake, we defer to the historical nomenclature and will hereafter refer to GRP94 gp96 as GRP94. GRP94 bears a very high sequence similarity to cytosolic Hsp90 and...

Nk Cells And Tumor Cell Killing

Apart from their intracellular chaperoning functions, HSP have been found to play key roles in tumor immunity. Most immunotherapeutic approaches exploit the carrier function of HSP for tumor-derived peptides. Following cross-presentation of HSP-chaperoned peptides on MHC class I molecules (Arnold-Schild et al., 1999 Basu et al., 2001 Binder et al., 2000 Binder et al., 2004 Sondermann et al., 2000) an antigen-specific CD8+ T cell response is thus initiated (Binder et al., 2001 Doody et al., 2004...

Virus Induced Changes In Mhc Class I Presentation Of Hostderived Peptides

The MHC Class I Molecule and Virus Associated Stress Viral infection imposes stress upon infected cells resulting in up-regulation of host anti-viral factors and modification of host proteins involved in successful viral replication. Up-regulation and interaction with host-derived proteins during viral infection translates into an altered repertoire of host-derived ligands displayed by the MHC class I molecules on the surface of infected cells. Infection with HIV-1, measles virus, and influenza...

Hspapc Interactions Initiation Of Immune Responses

SRIVASTAVA Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030-1601 Abstract The immunogenicity of HSPs is exquisitely dependent on its interaction with professional antigen presenting cells. The interaction is specific and occurs through surface receptors on the APC such as CD91. Other molecules such as CD40, LOX-1, CD36, Toll-like receptor-2 & 4, SR-A and SREC-I have also been...

Tumor Induced Changes In Mhc Class I Presentation Of Hostderived Peptides

The MHC Class I Molecule and Tumor Associated Stress Tumor cells experience a number of cellular stresses that translate into genetic mutations and altered gene expression and protein processing. Mutations in proteins involved in cell signaling, tumor suppression and DNA repair can lead to constitutive signaling, abnormal cell proliferation, and accumulation of numerous mutations resulting in genome wide instability. Genetic instability is detrimental to any cell but particular levels of...

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0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Days after Colo357(o.t.) injection Figure 3. Overall survival of tumor-bearing SCID beige mice treated either with PBS (control) or with IL-2 TKD-activated T or NK cells. Mice were immunoreconstituted by i.v. injection into the tail vein on day 15 after tumor cell inoculation and therefore might be of clinical relevance. We also demonstrated that NK cells stimulated with IL-2 TKD have the capacity to eradicate Hsp70 membrane-positive tumors in vitro...

The Antiinflammatory Properties Of Gp96

Although gp96 has been reported to have pro-inflammatory effects and to induce peptide-specific protective immunity (summarised above), anti-tumour immunity is not apparent when high doses of the protein are administered. Indeed, it has been demonstrated that high-dose gp96 can attenuate inflammatory disease and delay skin transplant rejection (Chandawarkar, Wagh, Kovalchin and Srivastava 2004, Chandawarkar et al., 1999, Kovalchin, Mendonca, Wagh, Wang and Chandawarkar 2006). The...

Heat Shock Proteins As Targets For Immune Cells

Once HSP appear on the cell surface, they are accessible to the immune surveillance system. HSP expressed on cell surfaces can elicit strong immune responses, as these molecules contain several highly conserved epitope sequences with strong immunogenic properties (Kaufmann and Schoel, 1994 Shinnick, 1991 Zugel and Kaufmann, 1999). On the other hand, an overzealous immune response to HSP can have several undesirable effects. Due to high degree of phylogenic conservation, HSP species of microbial...

Heat Shock Proteins As Vaccine Vehicles

T cell epitopes derived from exogenous antigens and endocytosed by APCs are mainly loaded into the MHC II molecules for recognition by CD4+ T cells. In contrast, endogenous antigens (i.e. auto-antigens and viral proteins) are presented in the context of MHC class I molecules to CD8+ T cells. Antigen-primed CD4+ and CD8+ T cells then differentiate into effector T helper (Th) and cytotoxic T cells, respectively. Depending on their polarization (determined on the panel of cytokines they produce),...

From Bench To Bedside

Previous reports on different animal models revealed that IL-2-activated NK cells are able to induce regression of established lung and liver tumors and metastases of different origin (Schwarz et al., 1989 Vujanovic et al., 1995 Whiteside et al., 1998 Yasumura et al., 1994). The control of tumors and metastases corresponded with an extended life expectancy. In contrast, the injection of IL-2 alone was significantly less efficient compared to an adoptive transfer of IL-2-activated NK cells....

Release Of Heat Shock Proteins Passive Versus Active Release Mechanisms

Division of Investigative Pathology, Scott & White Memorial Hospital and Clinic and The Texas A& M University System Health Science Center College of Medicine, Temple, Texas, USA Abstract There is now no doubt that heat shock proteins have a profound immunoregulatory effect on the host's immune system. This knowledge has successfully been harnessed to generate a number of important clinical trails. However, one intriguing question that remains to be answered is how heat shock proteins...

Adaptive Vs Innate Immune Systems

The immune system is an organization of cells and molecules with specialized roles in defending against infection. There are two fundamentally different types of responses to invading microbes. Innate (natural) responses occur to the same extent however many times the infectious agent is encountered, whereas acquired (adaptive) responses improve on repeated exposure to a given infection. The innate responses use phagocytic cells (neutrophils, monocytes, and macrophages), cells that release...

HSP Immune Responses and Lack of Self Tolerance

Besides their immunodominance as microbial antigens, under various circumstances HSP do elicit immune responses also when (over-)expressed as self antigens by cells or tissues. And this seems to be a peculiar feature of HSP, especially because in many cases immune responses to this self antigen are not associated with pathogenic autoimmunity. Evidently, healthy individuals have a broad repertoire of T and B cells with specificity for mammalian or self HSP. Self HSP specific immunity has been...

Magea1

MAGE-A1 is one of 12 CT gene products that have been identified in numerous tumor types. MAGE-A1 interacts with the SKIP adaptor protein and histone deacety-lases to effectively repress the transcriptional transactivation activity of Notch1-IC, which is involved in cell fate decisions (Laduron et al., 2004). As a transcriptional regulator MAGEA1 may play a significant role in tumorigenesis by altering gene expression patterns associated with a number of signaling pathways. The first MAGE-A1 MHC...

Infection

Infection of cells with a variety of microorganisms could result in cell death by apoptosis or necrosis (Fischetti, 2005 Gruenberg and van der Goot, 2006 Mathis et al., 2005 Thorne et al., 2005a Thorne et al., 2005b). Lytic viruses are known to induce necrotic cell death (Brinkmann and Schulz, 2006 O'Shea , 2005 O'Shea et al., 2005). Infection of SK29-Mel-1 with the lytic parvovirus H1 occurs in the absence of HLA class I or costimulatory molecule upregulation (Moehler et al., 2003). In...

Hsf1 Nurd Complex

Model for gene repression by the HSF1 MTA1 NuRD complex. In the ACTIVE state, DNA is in an open conformation due to recruitment of HATs and ATP dependent remodeling complexes SWI SNF , and RNA polymerase II is able to transcribe the sequence of the structural gene. HSF1 recruitment by, for instance exposure to heregulin brings associated MTA1 and HDACs to the promoter, which deacetylates histones, recruit nucleosomes and lead to a compacted chromatin conformation that contributes to...