title: The translocation of nuclear molecules during inflammation and cell death.
abstract: CONCLUSIONS
  Inflammation is a complex biological process that represents the body's response to infection and/or injury. Endogenous molecules that induce inflammation are called death- or damage-associated molecular patterns (DAMPs). Among cellular constituents with DAMP activity, nuclear molecules can stimulate pattern recognition receptors, including toll-like receptors (TLRs). Current research is elucidating the translocation of nuclear molecules during cell death and identifying novel anti-inflammatory approaches to block their DAMP activity.
  
  
  BACKGROUND
  High mobility group box protein 1 (HMGB1), a non-histone nuclear protein, can translocate from cells during immune cell activation and cell death. Depending on redox state, HMGB1 can interact with TLR4 although it can bind to molecules such as cytokines to trigger other receptors. DNA and histones, which are bound together in the nucleus, also have important immunological activity. For DNA, DAMP activity may vary depending upon the binding to molecules that affect cell entry and intracellular location. The role of nuclear molecules in disease has been established in animal models using antibodies as inhibitors.
  
  
  RESULTS
  Key issues about the DAMP activity of nuclear molecules relate to (i) the impact on function of biochemical modifications such as redox state and post-translational modification, and (ii) the composition and properties of complexes that nuclear molecules may form with other blood components to affect immunological activity.
  
  
  CONCLUSIONS
  With the recognition of the immunological activity of the products of dead cells, future studies will define the diversity and properties of nuclear molecules in the extracellular space and develop strategies to block their activity during inflammation.
authors: Medical Research Service, Durham VA Hospital, Department of Medicine, Duke University Medical Center , Durham, North Carolina.
authors: David S
authors: DS
authors: Pisetsky
mesh_terms: D000818:Animals; D016923:Cell Death / Q000276:immunology / Q000502:physiology*; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; D009687:Nuclear Proteins
references: Nature. 2007 Oct 4;449(7162):564-9
references: 17873860
references: Swiss Med Wkly. 2011 Aug 29;141:w13256
references: 21877298
references: Autoimmun Rev. 2010 Nov;10(1):35-7
references: 20659590
references: Nat Rev Immunol. 2009 Aug;9(8):535-42
references: 19556980
references: J Immunol. 2006 Dec 1;177(11):7889-97
references: 17114460
references: Cell Death Differ. 2008 Sep;15(9):1339-49
references: 18566602
references: J Immunol. 2012 Aug 15;189(4):2017-22
references: 22772444
references: EMBO Rep. 2004 Aug;5(8):825-30
references: 15272298
references: J Leukoc Biol. 2007 Jan;81(1):1-5
references: 17032697
references: J Interferon Cytokine Res. 2011 Dec;31(12):867-86
references: 22029446
references: Nat Immunol. 2006 Jan;7(1):49-56
references: 16341217
references: J Exp Med. 2008 Dec 22;205(13):3007-18
references: 19064698
references: Innate Immun. 2012 Oct;18(5):727-37
references: 22344226
references: Biomarkers. 2008 Mar;13(2):184-200
references: 18270870
references: Am J Pathol. 2004 May;164(5):1751-9
references: 15111321
references: J Am Soc Nephrol. 2012 Aug;23(8):1375-88
references: 22677551
references: Annu Rev Immunol. 2011;29:139-62
references: 21219181
references: Infect Immun. 2005 Apr;73(4):1907-16
references: 15784530
references: J Immunol. 2007 May 15;178(10):6495-503
references: 17475879
references: J Exp Med. 2000 Aug 21;192(4):565-70
references: 10952726
references: Cell. 2008 Dec 26;135(7):1161-3
references: 19109884
references: Nat Rev Cancer. 2011 Jun;11(6):426-37
references: 21562580
references: Arthritis Res Ther. 2008;10(5):218
references: 18947369
references: Science. 1999 Jul 9;285(5425):248-51
references: 10398600
references: J Leukoc Biol. 2009 Sep;86(3):655-62
references: 19564572
references: J Leukoc Biol. 2007 Jan;81(1):49-58
references: 16980512
references: Immunity. 2008 Jul 18;29(1):21-32
references: 18631454
references: J Immunol. 2011 Sep 1;187(5):2626-31
references: 21784973
references: Inflammation. 2004 Aug;28(4):221-9
references: 15673164
references: Nature. 2007 Jul 26;448(7152):501-5
references: 17618271
references: Thromb Haemost. 2000 Dec;84(6):1087-94
references: 11154118
references: Sci Transl Med. 2011 Mar 9;3(73):73ra19
references: 21389263
references: Blood. 2003 Sep 15;102(6):2243-50
references: 12775567
references: Mediators Inflamm. 2012;2012:315941
references: 22778496
references: Cell. 2004 Jan 23;116(2):259-72
references: 14744436
references: Clin Chem. 2003 Aug;49(8):1286-91
references: 12881444
references: J Clin Invest. 2009 Feb;119(2):305-14
references: 19164858
references: Crit Rev Clin Lab Sci. 2009;46(1):1-24
references: 19107649
references: Trends Immunol. 2007 Oct;28(10):429-36
references: 17845865
references: Immunity. 2011 May 27;34(5):637-50
references: 21616434
references: Clin Chem Lab Med. 2002 Oct;40(10):962-8
references: 12476933
references: Immunol Rev. 2011 Sep;243(1):61-73
references: 21884167
references: J Exp Med. 2012 Aug 27;209(9):1519-28
references: 22869893
references: Nat Immunol. 2007 May;8(5):487-96
references: 17417641
references: J Immunol. 2008 Feb 15;180(4):2531-7
references: 18250463
references: Mol Med. 2012 Mar 30;18:250-9
references: 22105604
references: Nat Rev Immunol. 2010 Dec;10(12):826-37
references: 21088683
references: Clin Immunol. 2003 Feb;106(2):139-47
references: 12672404
references: Sci Transl Med. 2011 May 11;3(82):82ra38
references: 21562230
references: Cell Immunol. 2004 May;229(1):31-40
references: 15331326
references: Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):114-8
references: 20123073
references: Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14055-60
references: 21844380
references: J Biol Chem. 2007 Jun 1;282(22):16336-44
references: 17403684
references: Mol Med. 2012 Mar 27;18:224-30
references: 22076468
references: Hepatology. 2011 Sep 2;54(3):999-1008
references: 21721026
references: Nat Rev Immunol. 2008 Apr;8(4):279-89
references: 18340345
references: Nature. 2011 May 22;474(7352):516-20
references: 21602827
references: Nat Rev Rheumatol. 2012 Jan 31;8(4):195-202
references: 22293756
references: Proteomics. 2010 Apr;10(7):1484-93
references: 20127695
references: J Innate Immun. 2010;2(5):406-21
references: 20505309
references: Am J Physiol Cell Physiol. 2006 Dec;291(6):C1318-25
references: 16855214
references: Nature. 2002 Jul 11;418(6894):191-5
references: 12110890
references: Nat Med. 2009 Nov;15(11):1318-21
references: 19855397
references: Immunology. 2005 May;115(1):55-62
references: 15819697
references: Nature. 2010 Mar 4;464(7285):104-7
references: 20203610
references: EMBO J. 2003 Oct 15;22(20):5551-60
references: 14532127