ß2 integrin-induced signal transduction events in human neutrophils

Fredrik Melander

Research output: ThesisDoctoral Thesis (compilation)

Abstract

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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Experimental Pathology, Malmö
Supervisors/Advisors
  • [unknown], [unknown], Supervisor, External person
Award date2003 Jan 24
Publisher
ISBN (Print)91-628-5518-2
Publication statusPublished - 2003

Bibliographical note

Defence details

Date: 2003-01-24
Time: 09:15
Place: Main lecture hall, Pathology, U-MAS

External reviewer(s)

Name: Laudanna, Carlo
Title: Dr
Affiliation: Verona, Italy

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Article: I Dib K, Melander F and Andersson T. (2001). Role of p190RhoGAP in ß2 integrin regulation of RhoA in human neutrophils. J.Immunol. May 15;166(10):6311-22.

Article: II Melander F, Andersson T and Dib K. (2002). The Fgr but not the Syk tyrosine kinase is a target for ß2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils. Biochem. J. In press.

Article: III Dib K, Melander F, Axelsson L, Dagher M-C, Aspenström P and Andersson T. Down-regulation of Rac activity during ß2 integrin-mediated adhesion of human neutrophils. Manuscript.

Article: IV Melander F, Andersson T and Dib K. ß2 integrin-induced serine phosphorylation of c-Cbl in adherent human neutrophils. Manuscript.

Subject classification (UKÄ)

  • Cancer and Oncology

Free keywords

  • Inflammation
  • integrins
  • signal transduction
  • Rho GTPases
  • kinases
  • c-Cbl
  • General pathology
  • patologisk anatomi
  • pathological anatomy
  • Patologi (allmän)
  • neutrophils

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