title: The inflammatory response to double stranded DNA in endothelial cells is mediated by NFκB and TNFα.
abstract: Endothelial cells represent an important barrier between the intravascular compartment and extravascular tissues, and therefore serve as key sensors, communicators, and amplifiers of danger signals in innate immunity and inflammation. Double stranded DNA (dsDNA) released from damaged host cells during injury or introduced by pathogens during infection, has emerged as a potent danger signal. While the dsDNA-mediated immune response has been extensively studied in immune cells, little is known about the direct and indirect effects of dsDNA on the vascular endothelium. In this study we show that direct dsDNA stimulation of endothelial cells induces a potent proinflammatory response as demonstrated by increased expression of ICAM1, E-selectin and VCAM1, and enhanced leukocyte adhesion. This response was dependent on the stress kinases JNK and p38 MAPK, required the activation of proinflammatory transcription factors NFκB and IRF3, and triggered the robust secretion of TNFα for sustained secondary activation of the endothelium. DNA-induced TNFα secretion proved to be essential in vivo, as mice deficient in the TNF receptor were unable to mount an acute inflammatory response to dsDNA. Our findings suggest that the endothelium plays an active role in mediating dsDNA-induced inflammatory responses, and implicate its importance in establishing an acute inflammatory response to sterile injury or systemic infection, where host or pathogen derived dsDNA may serve as a danger signal.
authors: Center for Engineering in Medicine and the Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Suraj J
authors: SJ
authors: Patel
authors: Rohit
authors: R
authors: Jindal
authors: Kevin R
authors: KR
authors: King
authors: Arno W
authors: AW
authors: Tilles
authors: Martin L
authors: ML
authors: Yarmush
references: Tissue Eng Part C Methods. 2011 Jan;17(1):113-22
references: 20684748
references: Nature. 2000 Dec 7;408(6813):740-5
references: 11130078
references: Nature. 2009 Mar 26;458(7237):514-8
references: 19158675
references: Acute Card Care. 2010 Sep;12(3):109-11
references: 20712451
references: Circ Res. 2001 May 11;88(9):903-10
references: 11348999
references: Annu Rev Immunol. 2002;20:55-72
references: 11861597
references: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9771-6
references: 20457908
references: Am J Physiol Regul Integr Comp Physiol. 2007 Oct;293(4):R1538-44
references: 17652366
references: N Engl J Med. 1990 Jul 5;323(1):27-36
references: 2113184
references: Nat Immunol. 2010 Nov;11(11):1005-13
references: 20871604
references: Nat Immunol. 2010 Nov;11(11):997-1004
references: 20890285
references: Curr Opin Immunol. 2008 Aug;20(4):383-8
references: 18573338
references: Immunity. 2006 Jan;24(1):93-103
references: 16413926
references: Curr Pharm Des. 2006;12(32):4229-45
references: 17100625
references: Circulation. 2003 Jul 1;107(25):3243-7
references: 12835407
references: Nature. 2007 Jul 26;448(7152):501-5
references: 17618271
references: Biomed Microdevices. 2005 Sep;7(3):213-22
references: 16133809
references: J Exp Med. 2003 Oct 6;198(7):1043-55
references: 14517278
references: J Infect Dis. 1998 Jun;177(6):1465-74
references: 9607821
references: J Clin Invest. 1985 Oct;76(4):1382-90
references: 2414319
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
references: 11717429
references: Nat Immunol. 2010 May;11(5):395-402
references: 20351692
references: J Immunol. 2010 Jul 15;185(2):818-21
references: 20562263
references: Nat Rev Immunol. 2010 Feb;10(2):123-30
references: 20098460
references: Blood. 2003 Apr 1;101(7):2652-60
references: 12456506
references: Nat Rev Immunol. 2007 Oct;7(10):803-15
references: 17893694
references: J Clin Invest. 2009 Feb;119(2):305-14
references: 19164858
references: Science. 2005 Sep 16;309(5742):1857-61
references: 16166517
references: J Exp Med. 2005 Nov 21;202(10):1333-9
references: 16301743
references: Arthritis Res. 2002;4 Suppl 3:S109-16
references: 12110129
references: Nat Immunol. 2006 Jan;7(1):40-8
references: 16286919
references: Science. 2005 Sep 16;309(5742):1854-7
references: 16166516
references: Nat Rev Immunol. 2008 Apr;8(4):279-89
references: 18340345
references: J Clin Invest. 2006 Aug;116(8):2262-71
references: 16886064
references: Nature. 1994 Dec 22-29;372(6508):739-46
references: 7997261
references: Nature. 2008 Mar 6;452(7183):103-7
references: 18288107
references: Immunity. 1999 Oct;11(4):443-51
references: 10549626
references: J Exp Med. 1992 May 1;175(5):1181-94
references: 1314883
references: Infect Immun. 2006 Oct;74(10):5425-32
references: 16988217
references: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12867-72
references: 19617563
references: J Exp Med. 1995 Nov 1;182(5):1213-21
references: 7595192