Innate immunity meets with cellular stress at the IKK complex: regulation of the IKK complex by HSP70 and HSP90.

Several research models have shown that if cellular stress induces the heat shock response then this will suppress the NF-kappaB-mediated inflammatory response. The NF-kappaB signaling pathway mediates both stress signals and innate immunity signals. Heat shock proteins HSP70 and HSP90 regulate several signaling cascades to maintain cellular homeostasis. Recent studies have revealed that HSP70 and HSP90 proteins regulate the function of the IKK complex which is the major activator of the NF-kappaB complex. The heat shock response can cause the dissociation of the IKK complex, composed of protein kinase subunits IKKalpha and IKKbeta and the regulatory unit NEMO, and inhibit the activation of NF-kappaB signaling. Suppression of immune signaling during cellular stress may be a useful feedback response for helping cells to survive tissue injury. Furthermore, IKKalpha and IKKbeta kinases are important activators of tumorigenesis and hence the inhibition of long-term activation of the IKK complex by HSP70 and HSP90 proteins may prevent cancer development during chronic inflammation.

[1]  C. Deutschman,et al.  Enhanced heat shock protein 70 expression alters proteasomal degradation of I&kgr;B kinase in experimental acute respiratory distress syndrome* , 2007, Critical care medicine.

[2]  S. Ghosh,et al.  NF-κB and the immune response , 2006, Oncogene.

[3]  B. Aronow,et al.  Essential Requirement of Apolipoprotein J (Clusterin) Signaling for IκB Expression and Regulation of NF-κB Activity* , 2003, Journal of Biological Chemistry.

[4]  R. Voellmy,et al.  Repression of Heat Shock Transcription Factor HSF1 Activation by HSP90 (HSP90 Complex) that Forms a Stress-Sensitive Complex with HSF1 , 1998, Cell.

[5]  M. Jäättelä,et al.  The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions , 2007, FEBS letters.

[6]  Brian D. Strahl,et al.  A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression , 2003, Nature.

[7]  M. Bianchi.  DAMPs, PAMPs and alarmins: all we need to know about danger , 2007, Journal of leukocyte biology.

[8]  S. Mariathasan,et al.  Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation , 2007, Nature Reviews Immunology.

[9]  S. C. Lakhotia,et al.  Heat shock genes — integrating cell survival and death , 2007, Journal of Biosciences.

[10]  S. Legrand-Poels,et al.  NF-κB activation by reactive oxygen species: Fifteen years later , 2006 .

[11]  R. Morimoto,et al.  The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. , 1992, Genes & development.

[12]  I. Cohen,et al.  Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[13]  N. Perkins,et al.  Integrating cell-signalling pathways with NF-κB and IKK function , 2007, Nature Reviews Molecular Cell Biology.

[14]  Dick D. Mosser,et al.  Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome , 2000, Nature Cell Biology.

[15]  Bernd Bukau,et al.  The Hsp70 and Hsp60 Chaperone Machines , 1998, Cell.

[16]  R. Gaynor,et al.  Heat Shock Protein 27 Association with the IκB Kinase Complex Regulates Tumor Necrosis Factor α-induced NF-κB Activation* , 2003, Journal of Biological Chemistry.

[17]  F. Breedveld,et al.  SYNOVIAL FLUID T CELL REACTIVITY AGAINST 65 kD HEAT SHOCK PROTEIN OF MYCOBACTERIA IN EARLY CHRONIC ARTHRITIS , 1988, The Lancet.

[18]  David A. Cheresh,et al.  Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin , 2007, Nature.

[19]  W. Welch,et al.  Stress-Induced Inhibition of the NF-κB Signaling Pathway Results from the Insolubilization of the IκB Kinase Complex following Its Dissociation from Heat Shock Protein 901 , 2005, The Journal of Immunology.

[20]  L. Neckers,et al.  Heat shock protein 90: The cancer chaperone , 2007, Journal of Biosciences.

[21]  S. Srinivasula,et al.  Negative regulation of cytochrome c‐mediated oligomerization of Apaf‐1 and activation of procaspase‐9 by heat shock protein 90 , 2000, The EMBO journal.

[22]  G. Courtois,et al.  Inhibition of NF-κB Activation by Peptides Targeting NF-κB Essential Modulator (NEMO) Oligomerization* , 2004, Journal of Biological Chemistry.

[23]  A. Sher,et al.  Cooperation of Toll-like receptor signals in innate immune defence , 2007, Nature Reviews Immunology.

[24]  P. Csermely,et al.  Pharmacological modulation of the heat shock response. , 2006, Handbook of experimental pharmacology.

[25]  Vinay Tergaonkar,et al.  NFκB pathway: A good signaling paradigm and therapeutic target , 2006 .

[26]  S. Pietrokovski,et al.  Hsp90 Recognizes a Common Surface on Client Kinases* , 2006, Journal of Biological Chemistry.

[27]  J. Simon,et al.  Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4* , 2004, Journal of Biological Chemistry.

[28]  A. Leonardi,et al.  NF-κB in solid tumors , 2006 .

[29]  H. Pahl,et al.  A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF‐kappa B. , 1995, The EMBO journal.

[30]  L. O’Neill,et al.  TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. , 2006, Trends in immunology.

[31]  J. Piette,et al.  NF-κB activation by double-strand breaks , 2006 .

[32]  F. Hartl.  Molecular chaperones in cellular protein folding , 1996, Nature.

[33]  M. Jäättelä,et al.  Heat shock proteins as cellular lifeguards. , 1999, Annals of medicine.

[34]  P. Srivastava,et al.  Roles of heat-shock proteins in antigen presentation and cross-presentation. , 2002, Current opinion in immunology.

[35]  C. Scheidereit,et al.  Requirement of Hsp90 activity for IκB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-κB activation , 2004, Oncogene.

[36]  Paul Workman,et al.  Inhibitors of the heat shock response: Biology and pharmacology , 2007, FEBS letters.

[37]  Gabriel Núñez,et al.  Intracellular NOD-like receptors in host defense and disease. , 2007, Immunity.

[38]  T. Vanden Berghe,et al.  The Journal of Cell Biology , 2002 .

[39]  J. Tschopp,et al.  The inflammasome: a danger sensing complex triggering innate immunity. , 2007, Current opinion in immunology.

[40]  D. Tang,et al.  THE INHIBITION OF LPS-INDUCED PRODUCTION OF INFLAMMATORY CYTOKINES BY HSP70 INVOLVES INACTIVATION OF THE NF-&kgr;B PATHWAY BUT NOT THE MAPK PATHWAYS , 2006, Shock.

[41]  Zhijian J. Chen.  Ubiquitin signalling in the NF-κB pathway , 2005, Nature Cell Biology.

[42]  M. Hinz,et al.  Signal Responsiveness of IκB Kinases Is Determined by Cdc37-assisted Transient Interaction with Hsp90* , 2007, Journal of Biological Chemistry.

[43]  S. Calderwood,et al.  Heat Shock Protein 70 Is Secreted from Tumor Cells by a Nonclassical Pathway Involving Lysosomal Endosomes1 , 2006, The Journal of Immunology.

[44]  Haichao Wang,et al.  The Anti-inflammatory Effects of Heat Shock Protein 72 Involve Inhibition of High-Mobility-Group Box 1 Release and Proinflammatory Function in Macrophages1 , 2007, The Journal of Immunology.

[45]  T. Suuronen,et al.  Geldanamycin activates Hsp70 response and attenuates okadaic acid-induced cytotoxicity in human retinal pigment epithelial cells. , 2005, Brain research. Molecular brain research.

[46]  W. Young,et al.  Alternative pathways of NF-kappaB activation: a double-edged sword in health and disease. , 2006, Cytokine & growth factor reviews.

[47]  Matthias Mann,et al.  IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation , 1997 .

[48]  Lu Zhang,et al.  Hsp70 promotes TNF-mediated apoptosis by binding IKKγ and impairing NF-κB survival signaling , 2004 .

[49]  J. Buchner.  Supervising the fold: functional principles of molecular chaperones , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  Bharat B. Aggarwal,et al.  Nuclear factor-κB: its role in health and disease , 2004, Journal of Molecular Medicine.

[51]  Myeong Sup Lee,et al.  Signaling pathways downstream of pattern-recognition receptors and their cross talk. , 2007, Annual review of biochemistry.

[52]  R. Kaufman,et al.  Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1α-Mediated NF-κB Activation and Down-Regulation of TRAF2 Expression , 2006, Molecular and Cellular Biology.

[53]  P. Lucas,et al.  An Induced Proximity Model for NF-κB Activation in the Nod1/RICK and RIP Signaling Pathways , 2000 .

[54]  J. Piette,et al.  Extending the nuclear roles of IκB kinase subunits , 2006 .

[55]  Richard B. Gaynor,et al.  Hsp27 association with the IKK complex regulates TNF-α-induced NF-κB activation , 2003 .

[56]  J. Pober,et al.  Tumor necrosis factor receptor-associated factors (TRAFs) , 2001, Oncogene.

[57]  Xiran Zhang,et al.  Hsp70 inhibits lipopolysaccharide‐induced NF‐κB activation by interacting with TRAF6 and inhibiting its ubiquitination , 2006, FEBS letters.

[58]  A. Blalock.  Surgical treatment of pulmonary stenosis. , 1947, Lancet.

[59]  M. Horton,et al.  Hyaluronan Fragments Act as an Endogenous Danger Signal by Engaging TLR21 , 2006, The Journal of Immunology.

[60]  D. McMillan,et al.  Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. , 1998, Circulation research.

[61]  D. Goeddel,et al.  TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. , 2002, Molecular cell.

[62]  J. Cobb,et al.  The Heat Shock Paradox: Does Nf-␬b Determine Cell Fate? Stress Response Interactions Are Implicated in Cellular and Organ Dysfunction , 2001 .

[63]  H. Helminen,et al.  Hsp70 accumulation in chondrocytic cells exposed to high continuous hydrostatic pressure coincides with mRNA stabilization rather than transcriptional activation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[64]  M. Tsan,et al.  Heat shock protein and innate immunity. , 2004, Cellular & molecular immunology.

[65]  G. Courtois,et al.  Complementation Cloning of NEMO, a Component of the IκB Kinase Complex Essential for NF-κB Activation , 1998, Cell.

[66]  R. Medzhitov,et al.  Innate immune recognition: mechanisms and pathways , 2000, Immunological reviews.

[67]  R. Morimoto,et al.  Role of the heat shock response and molecular chaperones in oncogenesis and cell death. , 2000, Journal of the National Cancer Institute.

[68]  H. Harris,et al.  Heat shock inhibits NF-kB activation in a dose- and time-dependent manner. , 2005, The Journal of surgical research.

[69]  M. Karin,et al.  The two NF-κB activation pathways and their role in innate and adaptive immunity , 2004 .

[70]  P. Srivastava,et al.  Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. , 2000, International immunology.

[71]  J. Buchner,et al.  Hsp90: Chaperoning signal transduction , 2001, Journal of cellular physiology.

[72]  H. Pahl.  Activators and target genes of Rel/NF-κB transcription factors , 1999, Oncogene.

[73]  N. Kitteringham,et al.  Plasticity in cell defence: access to and reactivity of critical protein residues and DNA response elements , 2006, Journal of Experimental Biology.

[74]  G. Courtois,et al.  NEMO Trimerizes through Its Coiled-coil C-terminal Domain* , 2002, The Journal of Biological Chemistry.

[75]  David M. Rothwarf,et al.  A cytokine-responsive IκB kinase that activates the transcription factor NF-κB , 1997, Nature.

[76]  F. Martinon,et al.  NLRs join TLRs as innate sensors of pathogens. , 2005, Trends in immunology.

[77]  Toby Lawrence,et al.  IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation , 2005, Nature.

[78]  B. Aggarwal,et al.  Nuclear factor-kappaB: a friend or a foe in cancer? , 2004, Biochemical pharmacology.

[79]  S. Akira,et al.  Toll-like receptors and innate immunity , 2006, Journal of Molecular Medicine.

[80]  M. Omata,et al.  Cutting Edge: The IκB Kinase (IKK) Inhibitor, NEMO-Binding Domain Peptide, Blocks Inflammatory Injury in Murine Colitis1 , 2007, The Journal of Immunology.

[81]  R. Currie,et al.  Heat shock paradox and a new role of heat shock proteins and their receptors as anti-inflammation targets. , 2007, Inflammation & allergy drug targets.

[82]  G. Hortobagyi,et al.  IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway , 2007, Cell.

[83]  R. Medzhitov,et al.  Innate immunity--cross-talk with adaptive immunity through pattern recognition receptors and cytokines. , 2007, Current opinion in immunology.

[84]  Y. Masuda,et al.  Involvement of Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) in Apoptosis Induced by β-Hydroxyisovalerylshikonin* , 2004, Journal of Biological Chemistry.

[85]  C. Ramana,et al.  The Role of Hsp90N, a New Member of the Hsp90 Family, in Signal Transduction and Neoplastic Transformation* , 2002, The Journal of Biological Chemistry.

[86]  V. Malhotra,et al.  Interactions between the heat shock response and the nuclear factor-kappaB signaling pathway. , 2002, Critical care medicine.

[87]  P. Srivastava,et al.  Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. , 1999, Journal of immunology.

[88]  L. Weber,et al.  Sequence and regulation of a gene encoding a human 89-kilodalton heat shock protein , 1989, Molecular and cellular biology.

[89]  Tomohiro Watanabe,et al.  Signalling pathways and molecular interactions of NOD1 and NOD2 , 2006, Nature Reviews Immunology.

[90]  R. Kiessling,et al.  Induction of heat shock protein in monocytic cells by oxidized low density lipoprotein. , 1996, Atherosclerosis.

[91]  M. Santoro,et al.  Heat shock factors and the control of the stress response. , 2000, Biochemical pharmacology.

[92]  Claus Scheidereit,et al.  IκB kinase complexes: gateways to NF-κB activation and transcription , 2006, Oncogene.

[93]  S. Koyasu,et al.  Autoantibodies to the heat-shock protein hsp90 in systemic lupus erythematosus. , 1988, The Journal of clinical investigation.

[94]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[95]  J. Tschopp,et al.  Signals from within: the DNA-damage-induced NF-κB response , 2006, Cell Death and Differentiation.

[96]  J. Winfield,et al.  Brief Definitive Report AUTOANTIBODIES TO THE CONSTITUTIVE 73-kD MEMBER OF THE hsp70 FAMILY OF HEAT SHOCK PROTEINS IN SYSTEMIC LUPUS ERYTHEMATOSUS , 2022 .