Signaling capacity of ß2-integrins in relations to neutrophil motility
1996 (English)Licentiate thesis, comprehensive summary (Other academic)
The neutrophil granulocyte is one of the most mobile cell types in the human body and represents the first line of defense against invading pathogens. Adhesion and chemotactic receptors on the cell surface work together through modulations of the cytoskeleton and thereby cause the cell to move. Cell movement is dependent on actin reorganization but our understanding of the molecular mechanisms behind this is limited. The aim of the present thesis was to investigate the signaling capacity of the ß2-integrins and to try to define a signaling event responsible for the regulation of actin assembly in human neutrophils.
Stimulation with the chemotactic peptide fMetLeuPhe causes activation of a pertussis toxin-sensitive GTP-binding protein (G-protein) that in turn triggers a cascade of events in the human neutrophil. fMetLeuPhe stimulates an increase in filamentous actin (F-actin) and activation of the phosphatidylinositol 3-kinase (PI3-kinase) and the subsequent formation of phosphatidylinositol trisphosphate (PIP3). A role for PIP3 in promoting actin assembly has been suggested since the time course for PIP3 formation directly correlates with actin polymerization. The present study shows that engagement of ß2-integrins by antibody cross-linking induced a calcium signal and actin polymerization, but these responses, however, were not sensitive for pertussis toxin. The F-actin response induced by fMetLeuPhe was rapidly declining whereas the response induced by engagement of ß2-integrins was more sustained. This can be due to the inability of ß2-integrins to induce a cAMP signal since direct addition of cAMP and 1-isobutyl-methylxantine (IBMX, a phophodiesterase inhibitor) to electropermeabilized neutrophils caused a prompt reversal of the ß2-integrininduced F-actin elevation. The signaling capacity of the ß2-integrins was positively modulated by pretreatment of the cells with phorbol 12-myristate 13-acetate (PMA, a protein kinase C activating agent). Priming neutrophils with lnM PMA, a low concentration that did not influence the F-actin content per se, increased the magnitude of the ß2-integrin-induced F-actin response. Interestingly, engagement of ß2-integrins was shown to induce formation of PIP3 a fmding that further supports the suggested role for PIP3 in promoting actin polymerization.
Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1996. , 37 p.
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 22
Social Sciences Interdisciplinary
IdentifiersURN: urn:nbn:se:liu:diva-28173Local ID: 12994ISBN: 91-7871-759-0OAI: oai:DiVA.org:liu-28173DiVA: diva2:248724
Papers, included in licentiate theses, are not registered and included in the posts from 1999 and earlier.2009-10-082009-10-082015-03-18