Ao.Univ. Prof. Dr. Rainer de Martin
Department of Vascular Biology and Thrombosis Research
Center for Physiology and Pharmacology
Schwarzspanierstrasse 17, 1090 Vienna, Austria
Phone: +43 (0)1 40160 - 31161
Molecular Mechanisms of Inflammation
The acute inflammatory response is essentially a beneficial reaction of the organism to various kinds of noxae, including microbial, but also physical, chemical, or mechanical stimuli, e.g., burn, frost bite, trauma, or tissue necrosis. It is conceivable that such a powerful response requires tight control, since its destructive power may easily turn against structures of the organism. This is essentially what happens in chronic inflammation. Chronic inflammation is a hallmark of several diseases including those of the skin, the intestine, the joints, lung, central nervous system, and last not least the blood vessels. Unfortunately, it is very poorly understood how acute inflammation turns into a chronic state, and above all, that chronic inflammation is more refractory to treatment as compared to its acute form. One simple explanation is that the initiating stimulus persists, is either not efficiently removed or constantly re-generated. The other possibility is that the resolution phase is not or inappropriately initiated or conducted, i.e., that mechanisms of down-regulation are failing .
Our general aim is therefore the elucidation of the molecular mechanisms of inflammation in vascular, especially endothelial cells. Model systems are mostly HUVEC that are stimulated with pro-inflammatory agents (TNFa, IL-1, CD40L,or LPS.
During the past years, we e have tried to obtain a broad overview over the genetic response in EC to inflammatory stimuli and consecutively focused on the transcription factor NF-kB as a main regulator of many of these genes. Studies covered contributions to the understanding of the signal transduction pathway that leads to its activation, as well as in vivo proof-of-concept studies.
A main topic has been the resolution of inflammation, as this represents a clinically important step that appears to be impaired when acute inflammation turns into a chronic state, a hallmark of many diseases. We have noted that already at early stages after stimulation the endothelium expresses genes with negative regulatory function that have the potential to shut down specific aspects of the inflammatory response. This includes the NF-kB inhibitor IkBa, but also A20, tristetraproline, or dual-specificity phosphatases. However, positive feedback mechanisms have been characterized as well, such as the role of the anti-apoptotic protein XIAP. As stated above, it is tempting to envisage that impairment of these negative feedback mechanisms could promote the transition from acute to chronic inflammation.
Present work focusses, in collaboration with the Department of Pharmacognosy/University of Vienna, on the identification of novel anti-inflammatory compounds from natural sources such as herbal extracts. It is directed on one hand towards the delineation of the molecular mechanism(s) underlying the anti-inflammatory activity, and on the other hand on the purification and identification of the responsible compounds to serve as lead structures for further optimization. It holds the promise of identifying novel therapeutic strategies to counter excessive and chronic inflammatory responses.
Deciphering regulatory patterns of inflammatory gene expression from interleukin-1-stimulated human endothelial cells.
Mayer H, Bilban M, Kurtev V, Gruber F, Wagner O, Binder BR, de Martin R. Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1192-8.
Resolution of inflammation: intracellular feedback loops in the endothelium.
Winsauer G, de Martin R. Thromb Haemost. 2007 Mar;97(3):364-9.
Cytokine-inducible expression in endothelial cells of an I kappa B alpha-like gene is regulated by NF kappa B.
de Martin R, Vanhove B, Cheng Q, Hofer E, Csizmadia V, Winkler H, Bach FH. EMBO J. 1993 Jul;12(7):2773-9.
Novel phosphorylation-dependent ubiquitination of tristetraprolin by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and tumor necrosis factor receptor-associated factor 2 (TRAF2). Schichl YM, Resch U, Lemberger CE, Stichlberger D, de Martin R. J Biol Chem. 2011 Nov 4;286(44):38466-77.
CD40L and TNF both activate the classical NF-κB pathway, which is not required for the CD40L induced alternative pathway in endothelial cells.
Seigner J, Basilio J, Resch U, de Martin R. Biochem Biophys Res Commun. 2018 Jan 1;495(1):1389-1394.
Peucedanum ostruthium Inhibits E-Selectin and VCAM-1 Expression in Endothelial Cells through Interference with NF-κB Signaling.
Lammel C, Zwirchmayr J, Seigner J, Rollinger JM, de Martin R. Biomolecules. 2020 Aug 21;10(9):1215.
LC-ESI-FT-MSn Metabolite Profiling of Symphytum officinale L. Roots Leads to Isolation of Comfreyn A, an Unusual Arylnaphthalene Lignan.
D'Urso G, Masullo M, Seigner J, Holper-Schichl YM, de Martin R, Plaza A, Piacente S. Int J Mol Sci. 2020 Jun 30;21(13):4671.