HSP60 Speaks to the Immune System in Many Voices

Quintana, Francisco J.; Cohen, Irun R.

doi:10.1002/9780470754030.ch8

Cited by 16 publications

(12 citation statements)

References 58 publications

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“…These data are consistent with previous studies indicating that transient exposure of pancreatic islets to high glucose increases the activities of antioxidant enzyme, such as Cu/Zn-SOD [25]. HSP60 and HSP27 are synthesized in large amounts when cells are exposed to stressful stimuli such as inflammation, infection, and exposure to oxidizing agents [26], [27], [28], [29]. We also identified down-regulation of catalase, which has important antioxidant functions.…”

Section: Discussionsupporting

confidence: 92%

Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation

et al. 2010

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BackgroundIn type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold.Methods and FindingsWe evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant.ConclusionsOur data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.

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Section: Discussionsupporting

confidence: 92%

Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation

et al. 2010

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“…The presence of antibodies with a short half-life, as demonstrated in this study, indicates that the IgG3 antibodies against human HSP60 are continuously stimulated and produced. Thus, as suggested in other studies [51,52], the response to human HSP60 seen in SpA patients (Figure 4A) seems to rely on the ability to quickly control and regulate this response. This may explain the decrease in high-level IgG3 against human HSP60 from 2006 to 2010 (Figure 6B) and the average decrease in disease parameters (Table 1).…”

Section: Discussionsupporting

confidence: 74%

IgG subclass antibodies to human and bacterial HSP60 are not associated with disease activity and progression over time in axial spondyloarthritis

et al. 2013

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IntroductionSpondyloarthritis (SpA), an interrelated group of rheumatic diseases, has been suggested to be triggered by bacterial infections prior to the development of an autoimmune response that causes inflammation of the spinal and peripheral joints. Because human heat shock protein 60 (HSP60), recently renamed HSPD1, and bacterial HSP60 are highly homologous, immunological cross-reactivity has been proposed as a mechanism of disease initiation. However, previous investigations of the humoral immune response to HSP60 in SpA patients have lacked determination of immunoglobulin G (IgG) subclasses and patient follow-up. In this study, we have focused on these parameters in a cohort of axial SpA patients with a well-established set of clinical characteristics, including MRI changes and human leukocyte antigen B27.MethodsIgG subclass antibodies (IgG1, IgG2, IgG3 and IgG4) against recombinant HSP60 of three reactive arthritis-related bacteria; human HSP60; and the microorganisms Chlamydia trachomatis and C. pneumoniae were determined by ELISA. Serum samples collected from 2004 to 2006 and in 2010 and 2011 from 39 axial SpA patients were analyzed and compared with samples from 39 healthy controls. The Mann-Whitney U test and Wilcoxon matched pairs test were used to compare the antibody levels in different and paired groups, respectively. P < 0.01 was considered significant. The Spearman nonparametric correlation was used to determine correlation between antibody levels and between antibody levels and the disease parameters.ResultsElevated levels of IgG1 and IgG3 to human HSP60 and IgG1 to HSP60 of Salmonella enterica Enteritidis were observed in SpA patients compared with healthy controls at both time points. The antibody levels were almost constant over time for IgG1, whereas high levels of IgG3 to human HSP60 tended to decrease over time. The antibody response to human HSP60 was predominantly of the IgG3 subclass, and patients with high levels of IgG3 to this antigen had low levels of IgG1, indicating an inverse association. Different IgG subclasses were produced against bacterial and human HSP60 in the same serum sample, IgG1 and IgG3, respectively, indicating that there was no cross-reaction.ConclusionsA significant association was observed between axial SpA and the presence of IgG1/IgG3 antibodies to human HSP60 and of IgG1 to S. enterica Enteritidis and C. trachomatis. Generation of antibodies to human HSP60 was independent of the presence of antibodies to bacterial HSP60. No association was observed between clinical and MRI changes with antibodies over time. Altogether, such antibodies do not reflect the disease activity in these patients.This study has been approved by the Regional Research Ethics Committee of Central Jutland, Denmark. Trial registration numbers: 20050046 and 20100083

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“…Under normal conditions, HSP60 acts as a molecular chaperone, assisting in polypeptide transposition, folding and assembly. When HSP60 is overexpressed or ectopically expressed under conditions of stress, HSP60 acts as a self-antigen, which is recognized by the immune system and causes an immune response (20). HSP60 also acts as a signal molecule, serving a role in signal transduction (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of heat shock protein 60 on matrine-suppressed microglial activation

Zhang

Hou

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Matrine (MT) is the primary active alkaloid separated from members of the Sophora genus. Previous studies have reported that MT has anti-inflammatory effects in the central nervous system (CNS). However, the underlying molecular mechanism of the neuroprotective effect of MT remains unclear, particularly the role of heat shock protein 60 (HSP60). Microglia are macrophages in the CNS that serve an essential role in the innate immune system by producing various proinflammatory and neurotoxic factors. In addition, HSP60 is released by activated microglia causing an autoimmune response. The present study aimed to investigate whether MT could inhibit the activation of microglia via suppressing the HSP60 signaling pathway. The results demonstrated that the expression and release of HSP60 in LPS-activated BV2 microglial cells was significantly decreased by MT treatment. Extracellular HSP60 is a ligand of toll like receptor 4 (TLR-4); thus, it was hypothesized that secreted HSP60 could bind to TLR-4 on microglia and activate the TLR-4 signaling pathway. As expected, western blotting and ELISA results revealed that MT significantly inhibited the LPS-induced increase in TLR-4, myeloid differentiation primary response protein MyD88, caspase-3 and tumor necrosis factor-α. In conclusion, the results of the present study provide a novel direction for the prevention and treatment of neurodegenerative diseases characterized by microglial activation.

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HSP60 Speaks to the Immune System in Many Voices

Cited by 16 publications

References 58 publications

Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation

Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation

IgG subclass antibodies to human and bacterial HSP60 are not associated with disease activity and progression over time in axial spondyloarthritis

Neuroprotective effect of heat shock protein 60 on matrine-suppressed microglial activation

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