SILENT: Signal transduction pathways in leukocyte transendothelial migration

• Research unit: EU RFP
• Project number: 99.0591

Key words (English)

Chemikine function in transendothelial migration

Alternative project number (English)

EU project number: QLG1-1999-01036

Research programs (English)

EU-programme: 5. Frame Research Programme - 1.1.6 The ageing population and disabilities

Short description (English)

See abstract

Partners and International Organizations (English)

Coordinator: Fondazione Centro S.R.del M.T., Milan (I)

Abstract (English)

Immunological protection largely depends on the mobility of leukocytes, which access sites of initiation of immune responses (lymph nodes, spleen) and sites of inflammation by means of traversing the wall of blood vessels (termed transendothelial migration). In terms of molecular mechanisms it is increasingly clear that adhesion molecules together with chemokines define the migratory cues for proper tissue retention and relocalization of leukocytes. The present EU proposal ('SILENT') focuses on molecular events that take place during the interaction of leukocytes with the endothelial cells (EC) of blood vessels. Workpackages of the Theodor-Kocher Institute include the study of chemokines, which promote leukocyte-EC interactions (WP1.06), and the analysis of novel housekeeping chemokines (WP2.06).
Peripheral blood lymphocytes migrate poorly in response to homeostatic chemokines despite the fact that the corresponding chemokine receptors are present. Work in progress (WP1.06) includes the analysis of the potential effect of T cell adhesion and endothelial cell transmigration on T cell migration to chemokines. We find that the treatment of peripheral blood T cells with stimulatory antibodies to integrins strongly modulates the efficacy, by which T cells migrate in response to chemokines. We conclude that integrin-mediated signaling events, which take place during transendothelial migration of blood T cells, play a crucial modulatory role in subsequent T cell migration. Therefore, chemokine-driven tissue localization of leukocytes requires a 'maturation' step that occurs during leukocyte extravasation.
Additional work in progress (WP2.06) deals with the characterization of a novel homeostatic (housekeeping) chemokine, termed BRAK. Its expression is restricted to dermal fibroblasts and keratinocytes in the skin and lamina propria cells in intestinal mucosa. Of note, and in contrast to all other known chemokines, BRAK is highly selective for CD14+ blood cells (subset of monocytes) and its activity is positively affected by treatment of monocytes with the inflammatory mediator prostaglandin E2. Collectively, we propose that BRAK controls the generation of antigen presenting cells (dendritic cells, macrophages) under homeostatic and possibly also inflammatory conditions by regulating the recruitment of corresponding precursors from peripheral blood.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 99.0591