The general interest of the group is the elucidation of molecular mechanisms of inflammation in the endothelium. Model systems are mostly HUVEC that are stimulated with pro-inflammatory cytokines (TNFa, IL-1) or LPS. Main questions are:
a. which genes are expressed during the inflammatory response ?
b. how is their expression regulated ?
c. how is the inflammatory reaction resolved/terminated ?
Work in the past has focussed on the first two questions, resulting in a broad overview over the genetic response in EC to inflammatory stimuli (Mayeret al, ATVB 2004), and to the identification of the transcription factor NF-kB as a main regulator of many of these genes, including in vivo proof-of-concept studies (Breuss et al. Circulation 2002, Cejna et al., Radiology 2002, Trescher et al., J. Am. Coll. Cardiol. 2003, Kopp et al, Blood 2004).
Presently, our main focus is on the concept of negative feedback mechanisms: this is based on the observation that upon inflammatory stimulation EC do not only express genes that are associated with the execution of inflammatory process (e.g., cell adhesion molecules, interleukins, etc.) but also proteins with inhibitory function, the most prominent example being IkBa, the inhibitor of NF-kB that shuts down NF-kB activity at later times. Thus, we hypothesize that already at early time points after stimulation EC set the stage for the later resolution of the inflammatory response. In our experiments, approx. 10% of all upregulated genes following IL-1 stimulation have potentially inhibitory function. Presently we have chosen to study the role of tristetraproline, a RNA-destabilizing protein with additional inhibitory activity towards NF-kB and JNK signaling, in more detail (Schichl et al., JBC 2009, 2011, 2014). Presently, the topic of endothelial cell activation is studied in the context of platelet-endothelial cell interactions.
Wiesner, C., Winsauer, G., Resch, U., Hoeth, M., Schmid, J.A., van Hengel, J., van Roy, F., Binder, B.R., and de Martin, R. (2008) a-Catulin, a Rho signaliing component, can regulate NF-kB through binding to IKK-ß, and confers resistance to apoptosis. Oncogene 27(15):2159-2169.
Schichl, Y., Resch, U., Hofer-Warbinek, R., de Martin, R. (2009). Tristetraprolin impairs p65/RelA nuclear translocation. J. Biol. Chem. 284(43):29571-81.
Schichl, YM, Resch, U, Lemberger, CE, Stichlberger, D, and de Martin, R. (2011) Novel phosphorylation-dependent Ubiquitination of Tristetraprolin by MEK kinase 1 (MEKK1) and TNF-receptor associated factor 2 (TRAF2). J. Biol. Chem. 286(44):38466-7
Hoeth, M, Niederleithner, H, Hofer-Warbinek, R, Bilban, M, Mayer, H, Wagner, O, Petzelbauer, P, de Martin, R. (2012) The transcription factor SOX18 regulates the expression of matrix metalloproteinase 7 and guidance molecules in human endothelial cells, PLoS One 7(1):e30982.
Resch U, Cuapio A, Sturtzel C, Hofer E, de Martin R, Holper-Schichl YM. (2014) Polyubiquitinated tristetraprolin protects from TNF-induced, caspase-mediated apoptosis. J. Biol. Chem. 289(36):25088-100.