ß2 integrin-induced signal transduction events in human neutrophils

Sammanfattning: Inflammation is a localized protective response in vascularized tissues and can be induced by microbial infection or cell and tissue injury. Polymorphonuclear neutrophils (PMN) are the most common white blood cells and are recognized as major cellular mediators of acute inflammation. PMN are highly mobile cells that possess regulated mechanisms for controlling the expression and activation of adhesion molecules such as selectins and integrins. This is crucial for their tethering and migration into inflammatory sites. Once in the tissue PMN can execute their important bacteriocidal functions that will not only kill microorganisms, but also cause potential tissue damage. This thesis work is focused on the intracellular signalling events that the ß2 integrins induce. In particular we focused on small GTPases of the Rho family, proteins that are key regulators of cytoskeletal rearrangements but also important for the production of bacteriocidal substances. We could show that the small GTPases Rho and Rac display opposing activities in PMN with activated ß2 integrins and we could also identify important signalling proteins responsible for this. Moreover, the ubiquitin ligase c-Cbl was also shown to be phosphorylated and activated in adherent PMNs and is suggested to play a key role in the signalling pathway induced by ß2 integrins. ß2 integrins, or enzymes involved in the signalling cascade this adhesion receptor activate, could represent potential targets to control inflammatory conditions where unwanted and tissue destructive accumulation of leukocytes occurs.