Phagocytic-receptor signaling in human neutrophils
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
The neutrophil granulocyte is one of the most mobile cells in the body and through a number of functions represents the first line of defense against invading pathogens. Adhesion and chemotactic receptors on the cell surface work together through modulation of the cytoskeleton, thereby enabling cell movement. Engulfment is facilitated by opsonization of the microbes with C3b or C3bi complement fragments or with immunoglobulins, proteins that respectively bind to complement receptors (CR) and Fey receptors (FcyR) on the neutrophil. The aim of the present study was to investigate the signal transduction properties of CR and FcyR on human neutrophils. In particular, the investigations focused on second messengers of importance for regulating actin polymerization and NADPH-oxidase activity. This was approached by selective activation of each receptor on non-adherent human neutrophils using specific antibodies that were either cross-linked or prefixed on bacterial particles.
Both stimulation with f.MetLeuPhe and engagement of CR3 caused an increase in filamentous actin (F-actin) and activation of phosphatidylinositol 3-klnase with the subsequent formation of phosphatidylinositol trisphosphate (PIP,). We found that the F-actin response mediated by fMetLenPhe and CR3 were different. The F-actin response induced by fMetLeuPhe declined rapidly whereas the response induced by engagement of CR3 was more sustained. This is hypothesized to be due to the inability of CR3 to induce a cAMP signal, since direct addition of cAMP and 1-isobutyl-methylxantine (IBMX, a phosphodiesterase inhibitor) to electropermeabilized neutrophils caused a prompt reversal of the CR3-induced F-actin elevation.
Engagement of CR3 and CR1 by antibody cross-linking induced a Ca2+ signal and phospholipase D (PLD) activation. Furthermore, the PLD response was potentiated by PMA pretreatment and was dependent on the form of ligand presentation. Both FcyR (FcyRITA and FcyRIIIB) and CR3 induced activation of NADPH-oxidase, a response that was dependent on intracellular Ca2+, tyrosine kinase activation and PLD activity. However, only FcyRllA induced a strong phosphorylation of p72''\ indicating that CR3 and FcyRliA might use different pathways leading to NADPH-oxidase activation.
Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1999. , 56 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 608
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-25685Local ID: 10061ISBN: 91-7219-562-2OAI: oai:DiVA.org:liu-25685DiVA: diva2:246233
1999-11-12, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Wymann, Matthias P., Doktor
Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.2009-10-082009-10-082012-07-31Bibliographically approved