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PubMed1999

Cutting edge: receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells.

Immunization with heat shock proteins (HSPs) induces Ag-specific CTL responses. The specificity of the immune response is based on peptides associated with HSPs. To investigate how exogenous HSP/peptide complexes gain access to the MHC class I-restricted Ag presentation pathway, we incubated the monocytic cell line P388D1 and the dendritic cell line D2SC/1 with gold-labeled HSPs gp96 and HSC70. We show that HSPs bind specifically to the surface of these APCs and are internalized spontaneously by receptor-mediated endocytosis, demonstrating the existence of specific receptors for HSPs on these cells. In addition, we observe colocalization of internalized HSPs and surface MHC class I molecules in early and late endosomal structures. These findings provide possible explanations for the immunogenicity of HSP/peptide complexes and for the transfer of HSP-associated peptides onto MHC class I molecules.

Animals↗

PubMed1987

Heat shock proteins in thermotolerance and other cellular processes.

Heat shock proteins appear to be causatively involved in the acquisition of thermotolerance in prokaryotes but not in eukaryotes. Further, the enhanced synthesis of hsps may be necessary for some cellular responses to stress but not others. In prokaryotic cells the development of thermotolerance, as measured by cell survival, is dependent upon protein synthesis. However, in eukaryotes, enhanced hsp synthesis following an inducing stress and prior to a subsequent heat shock is neither necessary nor sufficient for the development of thermotolerance as measured by colony-forming assays. The enhanced expression of hsps may be required for some mammalian cellular stress responses, such as the ability to reform both actin microfilament bundles and nucleolar morphology. These latter two thermotolerant responses have not been correlated with colony-forming ability. Future work should address the relationships between these various physiological responses to stress and determine if hsps function in some repair mode with regard to colony formation responses. Evidence is accumulating that hsps or their cognates may function in growth and differentiation in some manner as yet to be fully explained. Recent studies indicate that genes controlling cell division in E. coli may be linked to those of several stress regulons, and it would not be surprising to find a similar relationship in eukaryotes. At this time, it is important that studies investigating the role of hsps in stress and other cellular responses such as growth and differentiation define the specific gene (including its regulatory sequences) that encodes the protein being investigated, in order to avoid apparently contradictory and confusing reports of hsps expression.

Animals↗

PubMed1985

Comparison of labeled heat shock proteins in neuronal and non-neuronal cells of Aplysia californica.

Aplysia californica has been used to study the protein synthetic response of nervous tissue to stress induced by elevated temperatures. The abdominal and pleural ganglia as well as associated connectives were exposed to various temperatures for 30 min, labeled with [33S]methionine at room temperature, and then analyzed by sodium dodecyl sulfate gel electrophoresis. All cells examined responded to temperatures of greater than 31 degrees C by a reduction in levels of labeled actin, as well as by the enhanced labeling of proteins with apparent Mr of 70,000 and 110,000. Two-dimensional electrophoresis indicated that the molecular weight and isoelectric focusing properties are similar to the heat shock proteins (HSPs) observed in other systems. In addition to these major HSPs, heat-induced proteins with molecular weights ranging from 70,000 to 90,000 were highly labeled in the neurosecretory bag cells. Further cell type-specific differences in the protein synthetic response to elevated temperatures were revealed by quantitation of the major HSPs. Levels of labeled HSPs were significantly lower in ganglion cells as compared to the non-neuronal connective cells. In addition, the decrease in actin levels appeared to be less dramatic in the ganglion cells. Analysis of the cellular compartmentalization of HSPs suggests that both neurons and glia are capable of HSP synthesis. Studies in the squid have demonstrated that HSPs are transferred from adaxonal glia into the axoplasm (Tytell, M., S. G. Greenberg, and R. J. Lasek, unpublished observation).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

[Mammalian small stress proteins and responses to stress].

When cells are exposed to heat stress or chemical stress, expression of genes for heat shock proteins or stress proteins (HSPs) is enhanced and the proteins are accumulated in cells. The cells with increased HSPs exhibit tolerance against the additional stress. HSPs are expressed also in unstressed tissues or cells for essential biochemical cellular processes including growth and differentiation. Since the responses of HSPs in tissues to stress loaded to a whole living body are much more sensitive compared to those in cultured cells, it is suggested that endogenous factors modulate the stress-induced expression of HSPs. Here we summarize the responses of small HSPs (alpha crystallins, HSP27 and p20) to stress and their modifications by various factors.

Amino Acid Sequence↗

PubMed1997

Anti-heat shock proteins autoantibodies in autoimmune thyroiditis. Preliminary study.

No data are currently available on the humoral autoimmune response against self heat shock proteins (hsps) possibly occurring in patients suffering from autoimmune thyroid disorders. Therefore, a preliminary research was carried out to assess whether anti-self hsps autoantibodies are present in human autoimmune thyroiditis (AIT). Serum samples from 14 patients with AIT were tested both in western blotting and in ELISA for antibody binding to protein extracts of human cultured cells (both unstimulated and heat-shocked) as well as to purified hsp 73 and hsp 72. It was found that 7 out 14 (50%) patients with AIT have autoantibodies of the IgM isotype strongly reacting with hsps 73/72. By contrast, autoantibodies to hsps 73/72 were detected only occasionally in sera from patients suffering from non-autoimmune thyroid disorders (1 out 11) as well as in sera from healthy individuals (2 out 9). No obvious clinical differences were detected between AIT patients who had autoantibodies to hsps 72/73 and those who did not. Clearly, more patients would have to be examined to determine whether the anomalous anti-hsps 73/72 autoimmune response occurring in a significant proportion of patients with AIT is in some way related to the pathogenesis and/or to the progression of the disease.

Autoantibodies↗

PubMed1998

Heat shock treatment decreases the mortality of sepsis in rats.

Sepsis is an increasingly common and lethal diagnosis in hospitalized patients. In spite of the advances in antibiotics and medical equipment, the mortality rate has not been improved in the last decade. Recently, heat shock proteins (Hsps) have been well documented to play a self-protective role in almost all living cells under various pathological and physiological stresses through a mechanism known as thermotolerance or cross tolerance. The present study was designed to investigate the expression of Hsp72 and the protective role of pre-induction of Hsps in the mortality during different phases of sepsis. Adult male Sprague-Dawley rats were employed in the study. Sepsis was induced by cecal ligation and puncture (CLP). Heat shock treatment was performed 16 hrs before sepsis induction by heating the rats whole-bodily with an electric heating pad under general anesthesia. The mortality rates with time in both control and preheated groups were monitored. Hsp72 was detected by SDS-PAGE, Western blotting and immunostaining in the brain, heart, liver, kidney, lung, adrenal gland, muscle and lymphocytes. The results show that both early (9 hrs post-CLP) and late (18 hrs post-CLP) sepsis failed to increase the synthesis of Hsp72. Previous induction of Hsps by heat shock treatment significantly decreased the mortality rate of late sepsis. Applying a sufficient inducer to lymphocytes of late sepsis reversed the synthesis of Hsp72 from inactive state into an over-expressive situation in vitro. These results suggest that Hsps are involved in the pathogenesis of sepsis and the involvement of Hsps during the progression of sepsis could add to a first line of host defense against invasive pathogens. Searching for an acceptable agent or less invasive method that leads to increased Hsps expression may provide a means for better treatment of severe infection.

Animals↗

PubMed1999

Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96.

We have previously demonstrated that vaccination with heat shock proteins hsp70, hsp90, and gp96 elicits specific immunity against the tumor from which the hsps were purified. Although the association of tumor Ag peptides with these hsps have been suggested, the identification of the peptides or their precursors stripped from the hsps remained to be resolved. We show in this report that an Ld-restricted cytotoxic T lymphocyte epitope of a mouse leukemia RLmale symbol1 and its precursors are associated with the chaperones hsp90 and hsp70 in the cytosol and gp96 in the lumen of the endoplasmic reticulum. Hsp70 was associated with only final sized octamer, while hsp90 was found to associate with the octamer and two distinct precursor peptides. The gp96 was associated with the octamer and one of the two precursors. Thus, each of the hsps bound a distinct set of peptides. Our results have demonstrated for the first time that the hsps associate not only with final sized tumor Ag peptide but also with its precursors. The implication of this evidence is also discussed in terms of the roles of hsps in MHC class I Ag processing/presentation.

Animals↗

PubMed1998

Heat-shock proteins in axoplasm: high constitutive levels and transfer of inducible isoforms from glia.

To characterize heat-shock proteins (HSPs) of the 70-kDa family in the crayfish medial giant axon (MGA), we analyzed axoplasmic proteins separately from proteins of the glial sheath. Several different molecular weight isoforms of constitutive HSP 70s that were detected on immunoblots were approximately 1-3% of the total protein in the axoplasm of MGAs. To investigate inducible HSPs, MGAs were heat shocked in vitro or in vivo, then the axon was bathed in radiolabeled amino acid for 4 hours. After either heat-shock treatment, protein synthesis in the glial sheath was decreased compared with that of control axons, and newly synthesized proteins of 72 kDa, 84 kDa, and 87 kDa appeared in both the axoplasm and the sheath. Because these radiolabeled proteins were present in MGAs only after heat-shock treatments, we interpreted the newly synthesized proteins of 72 kDa, 84 kDa, and 87 kDa to be inducible HSPs. Furthermore, the 72-kDa radiolabeled band in heat-shocked axoplasm and glial sheath samples comigrated with a band possessing HSP 70 immunoreactivity. The amount of heat-induced proteins in axoplasm samples was greater after a 2-hour heat shock than after a 1-hour heat shock. These data indicate that MGA axoplasm contains relatively high levels of constitutive HSP 70s and that, after heat shock, MGA axoplasm obtains inducible HSPs of 72 kDa, 84 kDa, and 87 kDa from the glial sheath. These constitutive and inducible HSPs may help MGAs maintain essential structures and functions following acute heat shock.

Action Potentials↗

PubMed2004

Glial expression of the 90-kDa heat shock protein (HSP90) and the 94-kDa glucose-regulated protein (GRP94) following an excitotoxic lesion in the mouse hippocampus.

Heat shock proteins (HSPs) are immediately expressed in neuronal and glial cells under various stressful conditions and play a protective role through molecular chaperones. Although several studies have been focused on the expression of HSPs, little is known about HSP90s expression in glial cells under neuropathological conditions. In this study, we evaluated the expression pattern of the glial cell-related HSP90 and GRP94 proteins, following the induction of an excitotoxic lesion in the mouse brain. Adult mice received an intracerebroventricular injection of kainic acid; the brain tissue was then analyzed immunohistochemically for HSPs and double labeling using glial markers. HSPs expression was quantified by Western blot analysis. Excitotoxic damage was found to cause pyramidal cell degeneration in the CA3 region of the hippocampus. In the injured hippocampus, reactive microglia/macrophages expressed HSP90 from 12 h until 7 days postlesion (PL), showing maximal levels at day 1. In parallel, hippocampal reactive astrocytes showed the expression of GRP94 from 12 h until 7 days PL. In general, HSPs expression was transient, peaked at 1-3 days PL and reached basal levels by day 7. For the first time, our data demonstrate the injury-induced expression of HSP90 and GRP94 in glial cells, which may contribute to the mechanism of glial cell protection and adaptation in response to damage, thereby playing an important role in the evolution of the glial response and the excitotoxic lesion outcome. HSP90 may provide antioxidant protective mechanisms against microglia/macrophages, whereas GRP94 may stabilize the astroglial cytoskeleton and participate in astroglial antioxidant mechanisms.

Animals↗

PubMed1988

A heat shock protein localized to chloroplasts is a member of a eukaryotic superfamily of heat shock proteins.

We have isolated cDNA clones from soybean and pea that specify nuclear-encoded heat shock proteins (HSPs) which localize to chloroplasts. The mRNAs for these HSPs are undetectable at control temperatures, but increase approximately 150-fold during a 2-h heat shock. Hybridization-selection followed by in vitro translation demonstrates that these HSPs are synthesized as precursor proteins which are processed by the removal of 5-6.5 kd during import into isolated chloroplasts. The nucleotide sequence of the cDNAs shows the derived amino acid sequences of the mature pea and soybean proteins are 79% identical. While the predicted transit peptide encoded by the pea cDNA has some characteristics typical of transit sequences, including high Ser content, multiple basic residues and no acidic residues, it lacks two domains proposed to be important for import and maturation of other chloroplast proteins. The carboxy-terminal region of the chloroplast HSP has significant homology to cytoplasmic HSPs from soybean and other eukaryotes. We hypothesize that the chloroplast HSP shares a common structural and functional domain with low mol. wt HSPs which localize to other parts of the cell, and may have evolved from a nuclear gene.

Amino Acid Sequence↗

PubMed1986

Temperature ranges over which rainbow trout fibroblasts survive and synthesize heat-shock proteins.

Cultures of the rainbow trout fibroblast cell line RTG-2 withstood temperatures from 0 degrees C to 28 degrees C. At 0 degrees C and 28 degrees C, no proliferation occurred, but cells persisted for at least 7 days. If the cultures were placed back at 22 degrees C, proliferation returned to normal in those that had been kept at 0 degrees C but was reduced in cultures that had been kept at 28 degrees C. Above 28 degrees C, cultures survived for only short periods. If RTG-2 cells that were grown routinely at 22 degrees C were shifted to 26, 28, and 30 degrees C, heat shock proteins (hsps) of 100, 87, 70, 68, 60, 39, 27, and 19 kilodaltons were synthesized. Synthesis was most pronounced at 28 degrees C, and at this temperature hsp synthesis was maximal by 2 hr and had returned to control levels by 36 hr. Individual hsps were synthesized maximally at slightly different times and temperatures, but under all conditions hsps 87 and 70 were most abundant. If cultures were shifted to 24 degrees C or 32 degrees C, hsp synthesis was not observed. Neither the placement of cultures at 5 degrees C nor the shift of cultures that had been maintained at 0 degrees C or 5 degrees C back to 22 degrees C induced the synthesis of hsps. However, cultures incubated at 5 degrees C for 24 hr did synthesize hsps at 26 degrees C, 28 degrees C, and 30 degrees C.

Animals↗

PubMed1987

Thermal injury by laser pulses: protection by heat shock despite failure to induce heat-shock response.

Pulsed lasers produce a variety of therapeutically useful effects in tissues by thermal mechanisms. In contrast with conventional hyperthermia, pulsed lasers rapidly induce extremely high temperatures confined to small areas within the tissues. It is not established, however, how cellular damage and repair responses differ between conventional and pulsed laser-induced hyperthermia. We have addressed this question by examining the induction of cellular heat-shock proteins (HSPs) and protection by heat-shock response against pulsed laser vs conventional hyperthermia. Cultured human dermal fibroblasts at confluency were exposed to single microsecond, 10.6-microns-wavelength pulses from a pulsed CO2 laser at radiant exposures between 0 and 1.3 J/cm2. Cell monolayers were directly exposed after removal of overlying medium. Positive control for the ability of the cells to synthesize of HSPs was obtained by heating the cells for 20 min in a water bath at 45 degrees C or 47 degrees C. The cultures were then labeled with L-[35S] methionine (Met), and proteins analyzed by sodium dodecyl sulfate polyacrylamide and two-dimensional gel electrophoresis 2 hr after exposure. The morphological alterations induced by laser or heat were similar under phase contrast microscopy. Conventional heating induced a heat-shock response, with the appearance of HSPs 2 hours after heating. In contrast, synthesis of HSPs could not be detected following laser irradiation, even at exposures decreasing both cell viability and incorporation of [35S] Met into cellular protein. Pre-exposure of cells to temperatures which induced synthesis of HSPs, however, significantly decreased cell death induced by subsequent laser irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Line↗

PubMed2004

Restoration of heat shock protein70 suppresses gastric mucosal inducible nitric oxide synthase expression induced by Helicobacter pylori.

Heat shock proteins (HSPs) are crucial for the maintenance of cell integrity during normal cellular growth as well as during pathophysiological conditions. While functioning mainly as molecular chaperones, HSPs also appear to be involved in diverse biological activities, such as apoptosis, carcinogenesis, and cytoprotection from cytotoxic damage. Infection with Helicobacter pylori causes inflammation in the gastric mucosa, leading to gastritis, gastric ulcers, duodenal ulcer disease, and even gastric cancer, but the role of HSPs in H. pylori-associated gastropathy is not known. Using two-dimensional electrophoretic analysis, we have observed significant shifts in HSP profiles after H. pylori infection in RGM-1 cells. We therefore evaluated the effect of treatments that induce HSPs on H. pylori-induced inducible nitric oxide synthase (iNOS) expression. We found that H. pylori infection significantly attenuated the expression of HSP70, whereas exposure of cells to noncytotoxic heat shock or geranylgeranylacetone restored HSP70 expression, as well as suppressing the expression of iNOS, a major cause of H. pylori-induced gastric tissue damage. Our results suggest that induction of HSP70 confers cytoprotection against H. pylori infection by inhibiting the expression of iNOS. In conclusion, these results provide important insights into the flux in HSPs profiles in response to H. pylori infection and highlight the cytoprotective role of HSP70 in H. pylori infection.

Animals↗

PubMed1994

Characterization of high-molecular-mass heat shock proteins and 42 degrees C-specific heat shock proteins of murine cells.

There are two isoforms of high-molecular-mass heat shock protein (HMM-HSP), hsp105A and hsp105B, in murine FM3A cells. To characterize the HMM-HSPs, we here purified hsp105A and hsp105B, as well as 42 degrees C-specific HSPs that are specifically induced by continuous heating at 42 degrees C, from the cytoplasmic extracts of the FM3A cells heat-shocked at 42 degrees C for 8 h. Digestion of the hsp105A, hsp105B, and 42 degrees C-specific HSPs with lysyl endopeptidase generated 17,000-Da polypeptide fragments in common, and the N-terminal amino acid sequences of the fragments revealed a homology with those of the adenosine binding domain of hsp70 family proteins and actin. Thus, the two isoforms of hsp105 and the 42 degrees C-specific HSPs seemed to be very similar proteins having a ATP binding domain in common, and these HSPs may constitute a HMM-HSP family in murine cells.

Amino Acid Sequence↗

PubMed1998

Differential expression of heat shock proteins in normal and failing human hearts.

BACKGROUND: Heat shock proteins (hsp) constitute an endogenous stress response that protects cells from injury. Most work on these important proteins has focused on the immediate response to acute stress in cell culture systems and mammalian models of heart disease. Little is known about the expression of the hsps in human hearts. We were interested in whether there was increased expression of the hsps in heart failure, a setting of chronic, sustained stress. Five different hsps were examined: hsp27, hsp60, hsp72, hsc70 and hsp90. METHODS AND RESULTS: Three groups of explanted hearts were studied: dilated cardiomyopathy (DCM), ischemic cardiomyopathy (IHD), and normal controls. Western-blotting with a standard curve of purified protein on each blot was used to quantify the expression of the hsps. Hsp27 was increased almost two-fold in DCM compared to normal hearts, and was significantly greater than in IHD hearts. Levels of hsp60 were doubled in both DCM and IHD hearts (P < 0.05). Hsp72, hsc70 and hsp90 were not significantly changed. CONCLUSIONS: This study shows for the first time that differential changes in hsp levels occur in end-stage heart failure. Since hsps can render cells resistant to apoptosis, and are associated with the mitochondria and the cytoskeleton, which are known to be abnormal in heart failure, these studies may lead to new insights into the pathogenesis of cardiac decompensation.

Adult↗

PubMed2006

Heat shock proteins in immunity.

This chapter focuses on immunological effects of eukaryotic and microbial heat shock proteins (HSPs), with molecular weights of about 60, 70, and 90 kDa. The search for tumor-specific antigens resulted in the identification of HSPs. They have been found to elicit a potent anti-cancer immune response mediated by the adoptive and innate immune system. Following receptor-mediated uptake of HSP (HSP70 and gp96) peptide complexes by antigen-presenting cells and representation of HSP-chaperoned peptides by MHC class I molecules, a CD8-specific T cell response is induced. Apart from chaperoning immunogenic peptides derived from tumors, bacterial and virally infected cells, they by themselves provide activatory signals for antigen-presenting cells and natural killer (NK) cells. After binding of peptide-free HSP70 to Toll-like receptors, the secretion of pro-inflammatory cytokines is initiated by antigen-presenting cells and thus results in a nonspecific stimulation of the immune system. Moreover, soluble as well as cell membrane-bound HSP70 on tumor cells can directly activate the cytolytic and migratory capacity of NK cells. Apart form cancer, HSPs of different origins, with a molecular weight of about 60, 70, and 90 kDa, also play a pivotal role in viral infections, including human and simian immunodeficiency virus (HIV, SIV), measles, and choriomeningitis. Moreover, HSPs have been found to induce tolerance against autoimmune diseases. In summary, depending on their mode of induction, intracellular/extracellular location, cellular origin (eukaryote/prokaryote), peptide loading status, intracellular ADP/ATP content, concentration, and route of application, HSPs either exert immune activation as danger signals in cancer immunity and mediate protection against infectious diseases or exhibit regulatory activities in controlling and preventing autoimmunity.

Animals↗

PubMed1991

Alfalfa heat shock genes are differentially expressed during somatic embryogenesis.

We have isolated two cDNA clones (Mshsp18-1; Mshsp18-2) from alfalfa (Medicago sativa L.) which encode for small heat shock proteins (HSPs) belonging to the hsp17 subfamily. The predicted amino acid sequences of the two alfalfa proteins are 92% identical and a similar degree of homology (90%) can be detected between Mshsp18-2 and the pea hsp17. In comparison to various members of small HSPs from soybean amino acid sequence similarities of 80-86% were identified. The alfalfa HSPs share a homologous stretch of amino acids in the carboxy terminal region with hsp22, 23, 26 from Drosophila. This region contains the GVLTV motif which is characteristic of several members of small HSPs. At room temperature alfalfa hsp18 mRNAs were not detectable in root and leaf tissues but northern analysis showed a low level of expression in microcallus suspension (MCS). The transcription of Mshsp18 genes is induced by elevated temperature, CdCl2 treatment and osmotic shock in cultured cells. In alfalfa somatic embryos derived from MCS a considerable amount of hsp18 mRNA can be detected during the early embryogenic stages under normal culture conditions. The differential expression of these genes during embryo development suggests a specific functional role for HSPs in plant cells at the time of the developmental switch in vitro.

Amino Acid Sequence↗

PubMed1991

Sequence, identification and characterization of cDNAs encoding two different members of the 18 kDa heat shock family of Zea mays L.

Heat-shocked maize seedlings (cv. Oh43) synthesize a characteristic set of heat-shock proteins (hsps) which include an 18 kDa family containing at least six major isoelectric variants. A cDNA library was constructed from poly(A)+ RNAs isolated from the radicles of heat-shocked maize seedlings and screened with a DNA fragment from the theoretical open reading frame of a putative Black Mexican Sweet maize hsp18 genomic clone. Two clones, cMHSP18-3 and cMHSP18-9, were isolated, and the RNA transcripts generated from them were translated into proteins which immunoreact with antibodies directed against the maize 18 kDa hsps and exhibit the same electrophoretic characteristics as two different members of the 18 kDa hsp family. Nucleotide sequence analyses of the cDNAs in these clones reveal that their 5' and 3' untranslated regions exhibit 33-34% identity and that their protein encoding regions share 93% identity. The deduced amino acid sequences of these clones show 90% identity, and the apparent molecular masses and isoelectric points of these proteins agree with those established for two different 18 kDa hsps, numbered 3 and 6. This report substantiates that at least two of the 18 kDa hsps in maize are products of different but related genes. Moreover, it establishes that transcripts for these proteins accumulate during heat shock and that both their nucleotide and deduced amino acid sequences share extensive similarities with the class VI small hsps in soybean and with transcripts expressed during meiosis in Lilium.

Amino Acid Sequence↗