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CR3, FcγRIIA and FcγRIIIB induce activation of the respiratory burst in human neutrophils: the role of intracellular Ca2+, phospholipase D and tyrosine phosphorylation
Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
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1999 (engelsk)Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1452, nr 1, s. 46-59Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Human neutrophils express two different types of phagocytic receptors, complement receptors (CR) and Fc receptors. In order to characterize the different signaling properties of each receptor we have used non-adherent human neutrophils and investigated CR3, FcγRIIA and FcγRIIIB for their signaling capacity. Selective activation of each receptor was achieved by coupling specific antibodies to heat-killed Staphylococcus aureus particles, Pansorbins, through their Fc moiety. Despite the fact that these particles are not phagocytosed, we show that addition of Pansorbins with anti-CD18 antibodies recognizing CR3 induced prominent signals leading to a respiratory burst. Stimulation with anti-FcγRIIIB Pansorbins induced about half of the response induced by anti-CR3 Pansorbins, whereas anti-FcγRIIA Pansorbins induced an even weaker signal. However, FcγRIIA induced strong phosphorylation of p72syk whereas FcγRIIIB induced only a very weak p72syk phosphorylation. During CR3 stimulation no tyrosine phosphorylation of p72syk was seen. Both phospholipase D and NADPH oxidase activities were dependent on intracellular calcium. This is in contrast to tyrosine phosphorylation of p72syk that occurred even in calcium-depleted cells, indicating that oxygen metabolism does not affect p72syk phosphorylation. Inhibitors of tyrosine phosphorylation blocked the respiratory burst induced by both FcγRIIA and FcγRIIIB as well as CR3. This shows that tyrosine phosphorylation of p72syk is an early signal in the cascade induced by FcγRIIA but not by CR3.

sted, utgiver, år, opplag, sider
1999. Vol. 1452, nr 1, s. 46-59
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-25448DOI: 10.1016/S0167-4889(99)00112-3Lokal ID: 9894OAI: oai:DiVA.org:liu-25448DiVA, id: diva2:245777
Tilgjengelig fra: 2009-10-07 Laget: 2009-10-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert
Inngår i avhandling
1. Signal transduction in human phagocytic cells during phagocytosis, oxidative activation and apoptosis
Åpne denne publikasjonen i ny fane eller vindu >>Signal transduction in human phagocytic cells during phagocytosis, oxidative activation and apoptosis
2003 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Neutrophils and macrophages are professional phagocytic cells that play a crucial role in host defense against invading microorganisms. They bind to, internalize, and subsequently kill microbes with an arsenal of reactive oxygen metabolites and microbicidal agents. The microbes are recognized by cell surface receptors, mainly by the phagocytic receptors FcγR and complement receptor 3 (CR3) that recognize IgG and complement fragments C3b/C3bi, respectively. Microbial pathogens such as Salmonella typhimurium have developed sophisticated mechanisms to avoid the host defense system and enter the cells by invasion, mediated by a type III secretion system.

The objective of this thesis was to investigate the signaling pathways during receptor-mediated phagocytosis by FcγRIIa, FcγRIIIb and complement receptor 3 (CR3), or during invasion by Salmonella typhimurium in human phagocytic cells. We have focused on the intracellular signaling pathways controlling phagocytosis, production of reactive oxygen metabolites, and apoptosis. Paper I-III focus on signal transduction events triggered after ligation of CR3, FcγRIIa, and FcγRIIIb in human neutrophils. Both activation of CR3 and FcγR induced production of reactive oxygen metabolites (ROM), where CR3 induced the most prominent response. The ROM production was dependent on intracellular Ca2+, tyrosine kinase activation, and phospholipase D (PLD) activity. FcγRIIa induced a strong phosphorylation Syk, which was less pronounced following FcγRIIIb ligation, and absent after CR3 activation. Our data indicate that CR3 and FcγR activate different signaling pathways. By exposing neutrophils to TNF-α prior to ligation of CR3, the oxidative response was strongly enhanced, whereas the response to FcγR-ligation was unaffected. This increase was in part due to a p38 MAPK-dependent upregulation of CR3 on the cell surface, but also due to modulation of intracellular signaling pathways since Syk was activated by CR3 as well as FcγR in TNF-α treated cells. In contrast to macrophages where only FcγR activates Rac, Cdc42, and the subsequent ROM production, we show that CR3 as well as FcγR activate the GTPases Rac2 and Cdc42 in human neutrophils. Their downstream target p21 activated kinase was also activated, and Rac2 translocated to the membrane fraction. Correct function of these small GTP-binding proteins was necessary for generating a proper signal for ROM production in these cells.

One survival strategy exploited by microbial pathogens might be to induce apoptosis of tbe host. Invasive Salmonella typhimurium efficiently entered U937 cells and induced a pronounced degree of apoptosis in contrast to its opsonized mutants, which were internalized by receptor-mediated phagocytosis but failed to induce apoptosis. Invasion by Salmonella typhimurium activated Rac1 and Cdc42 independently of PI3 K and tyrosine kinase activation. Inhibition of Racl and Cdc42 inhibited both invasion and the induction of apoptosis. Receptor-mediated phagocytosis activated the survival signals Akt/PKB which protected the cells from apoptosis. Thus, control of apoptosis is a fine tuned balance between pro- and anti-apoptotic signaling proteins.

sted, utgiver, år, opplag, sider
Linköping: Linköpings universitet, 2003. s. 58
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 789
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-26651 (URN)11216 (Lokal ID)91-7373-548-5 (ISBN)11216 (Arkivnummer)11216 (OAI)
Disputas
2003-05-09, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (svensk)
Opponent
Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2012-10-09bibliografisk kontrollert

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