Chemokines, basic proteins that strongly bind to heparin, can induce leukocyte chemotaxis and activation and are intimately involved in various biological processes, including inflammatory responses, hematopoietic regulation and neoangiogenesis 18–20. The chemokines CCL4, CCL5 and CCL20 have been reported as being capable of attracting memory/activated T cells, www.selleckchem.com/products/r428.html whereas immature DC and B cells express

CCR6 – its specific CC chemokine receptor 20, 21. Previous DNA microarray analysis has revealed that IFI16 overexpression in EC triggers the expression of proinflammatory adhesion molecules, and functional analysis of the ICAM-1 promoter by site-specific mutagenesis has demonstrated that NF-κB is the main mediator of IFI16-driven gene induction 9. However, definitive prove that IFI16 regulates the proinflammatory activity of EC at the functional level has been missing. In this study, protein array analysis of the IFI16 secretome reveals that

IFI16 triggers the expression of both intercellular adhesion molecules and chemokines responsible for leukocyte recruitment in vivo. Consistent with these observations, significant increases in the protein levels of CCL4, CCL5 and CCL20 were identified by ELISA in the supernatants of HUVEC overexpressing IFI16. Moreover, studying CCL20 as a representative chemokine, we demonstrate that NF-κB is the relevant mediator of CCL20 gene transcriptional activation following IFI16 overexpression. The relevance of this interaction is highlighted by the finding that the supernatants of IFI16-overexpressing HUVEC trigger the migration of both Rapamycin supplier CCR6-positive L-DC and B cells and that this migration is significantly downregulated by the addition of Ab that neutralize CCL4, CCL5 and CCL20. Inflammation is a complex defence mechanism, which aims to contain and resolve harmful processes

(such as infections, toxic Myosin stress and tissue damage) and protect the integrity of the human body. At sites of inflammation, infection or vascular injury, both local proinflammatory and pathogen-derived stimuli render the vessel endothelium surface attractive for incoming leukocytes 22. This innate immune response of the endothelium consists of a well-defined and regulated multi-step cascade involving consecutive steps of release of leukocyte-recruiting chemokines by EC and adhesive interactions between the leukocytes and the endothelium; thus the proinflammatory activation of EC is important for the tight regulation of the mechanisms underlying the chemoattraction of leukocytes to lesions – mechanisms that are known to involve components of the NF-κB complex; indeed, the NF-κB complex is considered to be the major transcription factor regulating the expression of EC adhesion molecules and chemokine release 23–25. Consistent with this, in this study we show that IFI16 triggers the expression of proinflammatory genes by activating the NF-κB complex.