Toll-like Receptor Agonists and Febrile Range Hyperthermia Synergize to Induce Heat Shock Protein 70 Expression and Extracellular Release

Gupta, Aditi; Cooper, Zachary A.; Tulapurkar, Mohan E.; Potla, Ratnakar; Maity, Tapan K.; Hasday, Jeffrey D.; Singh, Ishwar

doi:10.1074/jbc.m112.427336

Cited by 63 publications

(65 citation statements)

References 75 publications

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“…However, it remains unclear how poly(I:C), a TLR3 ligand, increases Hsp27 and Hsp70 levels in ischemic cerebral tissue. Recent reports have shown that poly(I:C) cannot only induce Hsp70 expression but also promote the extracellular release of Hsp70 (44). It has also been reported that the signaling molecule IFN-b, which is downstream of TLR3, can upregulate the expression of Hsp70 in splenic dendritic cells (45).…”

Section: Discussionmentioning

confidence: 99%

Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3

Wang

Huang

Chen

et al. 2014

The Journal of Immunology

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Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B+ cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3−/− and TLR4−/−mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.

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Section: Discussionmentioning

confidence: 99%

Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3

Wang

Huang

Chen

et al. 2014

The Journal of Immunology

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“…Febrile temperatures can induce HSP70 expression and release by regulating signal transduction pathways, such as the mitogen-activated protein kinase (MAPK) (Gupta et al 2013), extracellular regulated kinase 1/2 (ERK 1/2), p38, and c-Jun amino (N)-terminal kinases 1/2 (JNK 1/2) (Cargnello and Roux 2011).…”

Section: Introductionmentioning

confidence: 99%

The regulation of TNFα production after heat and endotoxin stimulation is dependent on Annexin-A1 and HSP70

Nair

Arora

Lim

et al. 2015

Cell Stress and Chaperones

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Febrile temperatures can induce stress responses which protect cells from damage and can reduce inflammation during infections and sepsis. However, the mechanisms behind the protective functions of heat in response to the bacterial endotoxin LPS are unclear. We have recently shown that Annexin-1 (ANXA1)-deficient macrophages exhibited higher TNFα levels after LPS stimulation. Moreover, we have previously reported that ANXA1 can function as a stress protein.Therefore in this study, we determined if ANXA1 is involved in the protective effects of heat on cytokine levels in macrophages after heat and LPS. Exposure of macrophages to 42°C for 1 h prior to LPS results in an inhibition of TNFα production, which was not evident in ANXA1 −/− macrophages. We show that this regulation involves primarily MYD88-independent pathways. ANXA1 regulates TNFα mRNA stability after heat and LPS, and this is dependent on endogenous ANXA1 expression and not exogenously secreted factors. Further mechanistic studies revealed the possible involvement of the heat shock protein HSP70 and JNK in the heat and inflammatory stress response regulated by ANXA1. This study shows that ANXA1, an immunomodulatory protein, is critical in the heat stress response induced after heat and endotoxin stimulation.

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“…Therefore, HS response supports proteostasis (protein homeostasis) and cytoprotection [75]. Additionally, hyperthermia enhances toll-like receptor-4 (TLR4) expression and downstream signaling in vivo [84], whereas activation of TLR2, TLR3, and TLR4 acts synergistically with fever-associated hyperthermia to induce HSP70 expression and release to the extracellular space both in vivo and in vitro [85]. This means that, under microbial pathogenous attack, fever is even more protective because bacterial lipopolysaccharides (LPS) may signal to phagocytes via TLRs more efficiently, thus enhancing their microbicidal capacity.…”

Section: Anti-inflammatory Role Of Intracellular Hsp70mentioning

confidence: 99%

“…However, contrarily to that which occurs when HSP70 is within the intracellular space (iHSP70), when exported to the extracellular space (eHSP70), it functions as a stress signaling and pro-inflammatory molecule possibly by acting via TLR2 and TLR4 (see, for instance, ref. [85]). eHSP70 has been reported to be negatively correlated with intramuscular HSP70 content in obesity and diabetes [47].…”

Section: Anti-inflammatory Role Of Intracellular Hsp70mentioning

confidence: 99%

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

Leite

Cruzat

Krause

et al. 2016

Nutrire

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Aging is an intricate process modulated by different molecular and cellular events, such as genome instability, epigenetic and transcriptional changes, molecular damage, cell death and senescence, inflammation, and metabolic dysfunction. Particularly, protein quality control (chaperone systems) tends to be negatively affected by aging, thus leading to cellular senescence in metabolic tissues and, as a consequence, to the increasing dissemination of inflammation throughout the body. The heat shock (HS) response and its associated expression of the 70 kDa family of heat shock proteins (HSP70), which are anti-inflammatory molecular chaperones, are found to be markedly decreased during muscle inactivity and aging, while evidence supports the loss of HSP70 as a key mechanism which may drive muscle atrophy, contractile dysfunction, and reduced regenerative capacity. In addition, abnormal stress response is linked with higher incidence of neurodegenerative diseases as well as low-grade inflammatory diseases that are associated with physical inactivity and obesity. Therefore, strategies to increase or, at least, to maintain the levels of HSP70, and its accompanying HS response to stress, are key to reduce biological cell dysfunctions that occur in aging. In this sense, physical exercise is of note as it is the most powerful inducer of the HS response, comparable only to heat stress and fever-like conditions. On the other hand, the amino acid L-glutamine, whose production within the skeletal muscle and liberation into the blood stream is dependent on muscle activity, is a potentializer of HSP70 expression and HS response, particularly via its entering in hexosamine biosynthetic pathway (HBP). Herein, we discuss the collaborative role of glutamine (and its donors/precursors) and physical exercise (mostly responsible for glutamine release into the circulation) as potential tools to increase HSP70 expression and the HS response in the elderly.

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Toll-like Receptor Agonists and Febrile Range Hyperthermia Synergize to Induce Heat Shock Protein 70 Expression and Extracellular Release

Cited by 63 publications

References 75 publications

Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3

Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3

The regulation of TNFα production after heat and endotoxin stimulation is dependent on Annexin-A1 and HSP70

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

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