Skip to main content

Advertisement

Log in

Anti-inflammatory properties and pharmacological induction of Hsp70 after brain injury

  • Inflammation in acute and chronic neurological and psychiatric diseases
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

The 70-kDa heat shock protein (Hsp70) is thought to protect the brain from a variety of insults. Although the mechanism has been largely limited to its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory pathways. Brain injury and ischemia are associated with an immune response that is largely innate. Hsp70 appears to suppress this response and lead to improved neurological outcome. However, most of this work has relied on the use of genetic mutant models or Hsp70 overexpression using gene transfer or heat stress, thus limiting its translational utility. A few compounds have been studied by various disciplines which, through their ability to inhibit Hsp90, can cause induction of Hsp70. The investigation of Hsp70-inducing pharmacological compounds has obvious clinical implications in terms of potential therapies to mitigate neuroinflammation and lead to neuroprotection from stroke or traumatic brain injury. This review will focus on the inflammation modulating properties of Hsp70, and the current literature surrounding the pharmacological induction in acute neurological injury models with comments on potential applications at the clinical level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Adachi H, Katsuno M, Waza M, Minamiyama M, Tanaka F, Sobue G (2009) Heat shock proteins in neurodegenerative diseases: pathogenic roles and therapeutic implications. Int J Hyperth 25(8):647–654

    Article  CAS  Google Scholar 

  • Asea A (2008) Heat shock proteins and toll-like receptors. Handb Exp Pharmacol (183):111–127. doi:10.1007/978-3-540-72167-3_6

  • Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277(17):15028–15034. doi:10.1074/jbc.M200497200

    Article  PubMed  CAS  Google Scholar 

  • Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336(15):1066–1071

    Article  PubMed  CAS  Google Scholar 

  • Boll B, Eltaib F, Reiners KS, von Tresckow B, Tawadros S, Simhadri VR, Burrows FJ, Lundgren K, Hansen HP, Engert A, von Strandmann EP (2009) Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin’s lymphoma cells for natural killer cell-mediated cytotoxicity. Clin Cancer Res 15(16):5108–5116

    Article  PubMed  Google Scholar 

  • Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KM, Collins I, Davies NG, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L (2008) 4, 5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 51(2):196–218

    Article  PubMed  CAS  Google Scholar 

  • Candelario-Jalil E, Yang Y, Rosenberg GA (2009) Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158(3):983–994

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee A, Dimitropoulou C, Drakopanayiotakis F, Antonova G, Snead C, Cannon J, Venema RC, Catravas JD (2007) Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis. Am J Respir Crit Care Med 176(7):667–675

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee A, Snead C, Yetik-Anacak G, Antonova G, Zeng J, Catravas JD (2008) Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability. Am J Physiol Lung Cell Mol Physiol 294(4):L755–L763

    Article  PubMed  CAS  Google Scholar 

  • Cui X, Yu ZY, Wang W, Zheng YQ, Liu W, Li LX (2011) Co-inhibition of HSP70/HSP90 synergistically sensitizes nasopharyngeal carcinoma cells to thermotherapy. Integr Cancer Ther

  • Denes A, Thornton P, Rothwell NJ, Allan SM (2010) Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun 24(5):708–723

    Article  PubMed  CAS  Google Scholar 

  • Ding XZ, Fernandez-Prada CM, Bhattacharjee AK, Hoover DL (2001) Over-expression of hsp-70 inhibits bacterial lipopolysaccharide-induced production of cytokines in human monocyte-derived macrophages. Cytokine 16(6):210–219

    Article  PubMed  CAS  Google Scholar 

  • Feinstein DL, Galea E, Aquino DA, Li GC, Xu H, Reis DJ (1996) Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase expression by decreasing NFkappaB activation. J Biol Chem 271(30):17724–17732

    Article  PubMed  CAS  Google Scholar 

  • Gaston JS (2002) Heat shock proteins and innate immunity. Clin Exp Immunol 127(1):1–3 pii:1759

    Article  PubMed  CAS  Google Scholar 

  • Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ (2006) Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 49(15):4606–4615

    Article  PubMed  CAS  Google Scholar 

  • Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  PubMed  CAS  Google Scholar 

  • Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289(2):H558–H568. doi:10.1152/ajpheart.01275.2004

    Article  PubMed  CAS  Google Scholar 

  • Giffard RG, Yenari MA (2004) Many mechanisms for hsp70 protection from cerebral ischemia. J Neurosurg Anesthesiol 16(1):53–61 pii: 00008506-200401000-00010

    Article  PubMed  Google Scholar 

  • Giffard RG, Xu L, Zhao H, Carrico W, Ouyang Y, Qiao Y, Sapolsky R, Steinberg G, Hu B, Yenari MA (2004) Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury. J Exp Biol 207(Pt 18):3213–3220

    Article  PubMed  CAS  Google Scholar 

  • Giffard RG, Han RQ, Emery JF, Duan M, Pittet JF (2008) Regulation of apoptotic and inflammatory cell signaling in cerebral ischemia: the complex roles of heat shock protein 70. Anesthesiology 109(2):339–348

    Article  PubMed  CAS  Google Scholar 

  • Glaze ER, Lambert AL, Smith AC, Page JG, Johnson WD, McCormick DL, Brown AP, Levine BS, Covey JM, Egorin MJ, Eiseman JL, Holleran JL, Sausville EA, Tomaszewski JE (2005) Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance. Cancer Chemother Pharmacol 56(6):637–647

    Article  PubMed  CAS  Google Scholar 

  • Guzhova IV, Darieva ZA, Melo AR, Margulis BA (1997) Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells. Cell Stress Chaperones 2(2):132–139

    Article  PubMed  CAS  Google Scholar 

  • Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9(12):1512–1519. doi:10.1038/nn1805

    Article  PubMed  CAS  Google Scholar 

  • Henderson B (2010) Integrating the cell stress response: a new view of molecular chaperones as immunological and physiological homeostatic regulators. Cell Biochem Funct 28(1):1–14

    Article  PubMed  CAS  Google Scholar 

  • Heneka MT, Sharp A, Klockgether T, Gavrilyuk V, Feinstein DL (2000) The heat shock response inhibits NF-kappaB activation, nitric oxide synthase type 2 expression, and macrophage/microglial activation in brain. J Cereb Blood Flow Metab 20(5):800–811

    Article  PubMed  CAS  Google Scholar 

  • Hoshino T, Murao N, Namba T, Takehara M, Adachi H, Katsuno M, Sobue G, Matsushima T, Suzuki T, Mizushima T (2011) Suppression of Alzheimer’s disease-related phenotypes by expression of heat shock protein 70 in mice. J Neurosci 31(14):5225–5234

    Article  PubMed  CAS  Google Scholar 

  • Howard M, Roux J, Lee H, Miyazawa B, Lee JW, Gartland B, Howard AJ, Matthay MA, Carles M, Pittet JF (2010) Activation of the stress protein response inhibits the STAT1 signalling pathway and iNOS function in alveolar macrophages: role of Hsp90 and Hsp70. Thorax 65(4):346–353. doi:10.1136/thx.2008.101139

    Article  PubMed  Google Scholar 

  • Johnston JB, Jiang Y, van Marle G, Mayne MB, Ni W, Holden J, McArthur JC, Power C (2000) Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity. J Virol 74(16):7211–7220

    Article  PubMed  CAS  Google Scholar 

  • Jones Q, Voegeli TS, Li G, Chen Y, Currie RW (2011) Heat shock proteins protect against ischemia and inflammation through multiple mechanisms. Inflamm Allergy Drug Targ 10(4):247–259

    CAS  Google Scholar 

  • Kelly S, Yenari MA (2002) Neuroprotection: heat shock proteins. Curr Med Res Opin 18(Suppl 2):s55–s60

    Article  PubMed  Google Scholar 

  • Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26(24):6413–6421. doi:10.1523/JNEUROSCI.3815-05.2006

    Article  PubMed  CAS  Google Scholar 

  • Kwon HM, Kim Y, Yang SI, Kim YJ, Lee SH, Yoon BW (2008) Geldanamycin protects rat brain through overexpression of HSP70 and reducing brain edema after cerebral focal ischemia. Neurol Res 30(7):740–745

    Article  PubMed  CAS  Google Scholar 

  • Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97

    Article  PubMed  Google Scholar 

  • Lee JE, Kim YJ, Kim JY, Lee WT, Yenari MA, Giffard RG (2004) The 70 kDa heat shock protein suppresses matrix metalloproteinases in astrocytes. Neuroreport 15(3):499–502

    Article  PubMed  CAS  Google Scholar 

  • Leu JI, Pimkina J, Pandey P, Murphy ME, George DL (2011) HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells. Mol Cancer Res 9(7):936–947

    Google Scholar 

  • Lu A, Ran R, Parmentier-Batteur S, Nee A, Sharp FR (2002) Geldanamycin induces heat shock proteins in brain and protects against focal cerebral ischemia. J Neurochem 81(2):355–364

    Article  PubMed  CAS  Google Scholar 

  • Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, Busch DJ, Neely L, Sensintaffar JL, Yang YC, McKenzie A, Friedman J, Scannevin R, Kamal A, Hong K, Kasibhatla SR, Boehm MF, Burrows FJ (2009) BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Ther 8(4):921–929

    Article  PubMed  CAS  Google Scholar 

  • Madrigal-Matute J, Lopez-Franco O, Blanco-Colio LM, Munoz-Garcia B, Ramos-Mozo P, Ortega L, Egido J, Martin-Ventura JL (2010) Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis. Cardiovasc Res 86(2):330–337

    Article  PubMed  CAS  Google Scholar 

  • Manaenko A, Fathali N, Chen H, Suzuki H, Williams S, Zhang JH, Tang J (2010) Heat shock protein 70 upregulation by geldanamycin reduces brain injury in a mouse model of intracerebral hemorrhage. Neurochem Int 57(7):844–850

    Article  PubMed  CAS  Google Scholar 

  • Maridonneau-Parini I, Clerc J, Polla BS (1988) Heat shock inhibits NADPH oxidase in human neutrophils. Biochem Biophys Res Commun 154(1):179–186

    Article  PubMed  CAS  Google Scholar 

  • Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 54(1):34–66

    Article  PubMed  CAS  Google Scholar 

  • Messaoudi S, Peyrat JF, Brion JD, Alami M (2011) Heat-shock protein 90 inhibitors as antitumor agents: a survey of the literature from 2005 to 2010. Expert Opin Ther Pat 21(10):1501–1542

    Google Scholar 

  • Montaner J, Alvarez-Sabin J, Molina C, Angles A, Abilleira S, Arenillas J, Gonzalez MA, Monasterio J (2001) Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 32(8):1759–1766

    Article  PubMed  CAS  Google Scholar 

  • Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I (2004) Role of nitric oxide after brain ischaemia. Cell Calcium 36(3–4):265–275. doi:10.1016/j.ceca.2004.02.011

    Article  PubMed  CAS  Google Scholar 

  • Polla BS, Stubbe H, Kantengwa S, Maridonneau-Parini I, Jacquier-Sarlin MR (1995) Differential induction of stress proteins and functional effects of heat shock in human phagocytes. Inflammation 19(3):363–378

    Article  PubMed  CAS  Google Scholar 

  • Porter JR, Fritz CC, Depew KM (2010) Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Curr Opin Chem Biol 14(3):412–420

    Article  PubMed  CAS  Google Scholar 

  • Poulaki V, Iliaki E, Mitsiades N, Mitsiades CS, Paulus YN, Bula DV, Gragoudas ES, Miller JW (2007) Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis. Faseb J 21(9):2113–2123

    Article  PubMed  CAS  Google Scholar 

  • Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28(5):927–938. doi:10.1038/sj.jcbfm.9600582

    Article  PubMed  CAS  Google Scholar 

  • Ran R, Lu A, Zhang L, Tang Y, Zhu H, Xu H, Feng Y, Han C, Zhou G, Rigby AC, Sharp FR (2004) Hsp70 promotes TNF-mediated apoptosis by binding IKK gamma and impairing NF-kappa B survival signaling. Genes Dev 18(12):1466–1481

    Article  PubMed  CAS  Google Scholar 

  • Ransohoff RM (2009) Immunology: barrier to electrical storms. Nature 457(7226):155–156

    Article  PubMed  CAS  Google Scholar 

  • Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9(6):429–439. doi:10.1038/nri2565

    Article  PubMed  CAS  Google Scholar 

  • Roe SM, Prodromou C, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 42(2):260–266

    Article  PubMed  CAS  Google Scholar 

  • Sims JD, McCready J, Jay DG (2011) Extracellular heat shock protein (Hsp)70 and Hsp90alpha assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One 6(4):e18848

    Article  PubMed  CAS  Google Scholar 

  • Solit DB, Chiosis G (2008) Development and application of Hsp90 inhibitors. Drug Discov Today 13(1–2):38–43

    Article  PubMed  CAS  Google Scholar 

  • Spera PA, Ellison JA, Feuerstein GZ, Barone FC (1998) IL-10 reduces rat brain injury following focal stroke. Neurosci Lett 251(3):189–192

    Article  PubMed  CAS  Google Scholar 

  • Srivastava P (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2(3):185–194

    Article  PubMed  CAS  Google Scholar 

  • Sugawara T, Chan PH (2003) Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal 5(5):597–607. doi:10.1089/152308603770310266

    Article  PubMed  CAS  Google Scholar 

  • Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 36(4):305–315

    Article  PubMed  CAS  Google Scholar 

  • Trendelenburg G (2008) Acute neurodegeneration and the inflammasome: central processor for danger signals and the inflammatory response? J Cereb Blood Flow Metab 28(5):867–881. doi:10.1038/sj.jcbfm.9600609

    Article  PubMed  CAS  Google Scholar 

  • Turturici G, Sconzo G, Geraci F (2011) Hsp70 and its molecular role in nervous system diseases. Biochem Res Int:618127

  • Van Molle W, Wielockx B, Mahieu T, Takada M, Taniguchi T, Sekikawa K, Libert C (2002) HSP70 protects against TNF-induced lethal inflammatory shock. Immunity 16(5):685–695

    Article  PubMed  Google Scholar 

  • Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184(1–2):53–68

    Article  PubMed  CAS  Google Scholar 

  • Wang G, Krishnamurthy K, Tangpisuthipongsa D (2011) Protection of murine neural progenitor cells by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin in the low nanomolar concentration range. J Neurochem 117(4):703–711

    PubMed  CAS  Google Scholar 

  • Wegele H, Muller L, Buchner J (2004) Hsp70 and Hsp90—a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1–44. doi:10.1007/s10254-003-0021-1

    Article  PubMed  CAS  Google Scholar 

  • Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 91(18):8324–8328

    Article  PubMed  CAS  Google Scholar 

  • Wong CH, Crack PJ (2008) Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia–reperfusion injury. Curr Med Chem 15(1):1–14

    Article  PubMed  CAS  Google Scholar 

  • Yenari MA, Liu J, Zheng Z, Vexler ZS, Lee JE, Giffard RG (2005) Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection. Ann N Y Acad Sci 1053:74–83

    Article  PubMed  CAS  Google Scholar 

  • Yenari M, Kim JY, Kim N, Kacimi R (2011) Pharmacological induction of the 70 kD heat shock protein (HSP70): implications for cytoprotection. Neurology 76(Suppl 4):A449

    Google Scholar 

  • Yilmaz G, Granger DN (2008) Cell adhesion molecules and ischemic stroke. Neurol Res 30(8):783–793

    Article  PubMed  Google Scholar 

  • Yun CH, Yoon SY, Nguyen TT, Cho HY, Kim TH, Kim ST, Kim BC, Hong YS, Kim SJ, Lee HJ (2011) Geldanamycin inhibits TGF-beta signaling through induction of Hsp70. Arch Biochem Biophys 495(1):8–13

    Article  Google Scholar 

  • Zheng Z, Yenari MA (2004) Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res 26(8):884–892

    Article  PubMed  CAS  Google Scholar 

  • Zheng Z, Yenari MA (2006) The application of HSP70 as a target for gene therapy. Front Biosci 11:699–707 pii:1828

    Article  PubMed  CAS  Google Scholar 

  • Zheng Z, Kim JY, Ma H, Lee JE, Yenari MA (2008) Anti-inflammatory effects of the 70 kDa heat shock protein in experimental stroke. J Cereb Blood Flow Metab 28(1):53–63

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Yang GY, Ahlemeyer B, Pang L, Che XM, Culmsee C, Klumpp S, Krieglstein J (2002) Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci 22(10):3898–3909

    PubMed  CAS  Google Scholar 

Download references

Acknowlegments

This work was supported by grants to MY from the National Institutes of Health (NS40516), the Veteran’s Merit Award (1 I01 BX000589), and the Department of Defense (DAMD17-03-1-0532). Grants were administered by the Northern California Institute for Research and Education, and supported by resources of the Veterans Affairs Medical Center, San Francisco, California.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Midori A. Yenari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, N., Kim, J.Y. & Yenari, M.A. Anti-inflammatory properties and pharmacological induction of Hsp70 after brain injury. Inflammopharmacol 20, 177–185 (2012). https://doi.org/10.1007/s10787-011-0115-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-011-0115-3

Keywords

Navigation