The Inflammatory Response to Double Stranded DNA in Endothelial Cells Is Mediated by by NF\(\kappa\)B and TNF\(\alpha\)

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 NFkB and IRF3, and triggered the robust secretion of TNFa for sustained secondary activation of the endothelium. DNAinduced TNFa 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 dsDNAinduced 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. Citation: Patel SJ, Jindal R, King KR, Tilles AW, Yarmush ML (2011) The Inflammatory Response to Double Stranded DNA in Endothelial Cells Is Mediated by NFkB and TNFa. PLoS ONE 6(5): e19910. doi:10.1371/journal.pone.0019910 Editor: Holger K. Eltzschig, University of Colorado Denver, United States of America Received February 3, 2011; Accepted April 6, 2011; Published May 18, 2011 Copyright: 2011 Patel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: SJP was supported in part by a Department of Defense CDMRP Predoctoral Training Award. The work was supported by NIH BioMEMS Resource Center Grant P41 EB-002503, NIH Grant RO1AI063795, and a grant from the Shriners Hospital for Children. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work.