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

作者：Patel Suraj J^*; Jindal Rohit; King Kevin R; Tilles Arno W; Yarmush Martin L

来源：PLos One, 2011, 6(5): e19910.

DOI：10.1371/journal.pone.0019910

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 NF kappa B and IRF3, and triggered the robust secretion of TNF alpha for sustained secondary activation of the endothelium. DNA-induced TNF alpha 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.

• 出版日期2011-5-18