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Hyperglycemia-induced protein kinase C (PKC) activation inhibits phagocytosis of C3b- and IgG-opsonized yeast particles in normal human neutrophils
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
2003 (English)In: Experimental Diabesity Research, ISSN 1543-8600, E-ISSN 1543-8619, Vol. 4, no 2, 125-132 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate the effects of elevated glucose concentrations on complement receptor- and Fcgamma receptor-mediated phagocytosis in normal human neutrophils. D-Glucose at 15 or 25 mM dose-dependently inhibited both complement receptor- and Fcgamma receptor-mediated phagocytosis, as compared to that at a normal physiological glucose concentration. The protein kinase C (PKC) inhibitors GF109203X and Go6976 both dose-dependently and completely reversed the inhibitory effect of 25 mM D-glucose on phagocytosis. Complement receptor-mediated phagocytosis was dose-dependently inhibited by the cell permeable diacylglycerol analogue 1,2-dioctanoyl-sn-glycerol (DAG), an effect that was abolished by PKC inhibitors. Furthermore, suboptimal inhibitory concentrations of DAG and glucose showed an additive inhibitory effect on complement receptor-mediated phagocytosis. The authors conclude that elevated glucose concentrations can inhibit complement receptor and Fcgamma receptor-mediated phagocytosis in normal human neutrophils by activating PKCalpha and/or PKCbeta, an effect possibly mediated by DAG.

Place, publisher, year, edition, pages
2003. Vol. 4, no 2, 125-132 p.
Identifiers
URN: urn:nbn:se:umu:diva-4928DOI: 10.1155/EDR.2003.125PubMedID: 14630574OAI: oai:DiVA.org:umu-4928DiVA: diva2:144219
Available from: 2006-02-01 Created: 2006-02-01 Last updated: 2010-06-24Bibliographically approved
In thesis
1. Glucose and insulin modulate phagocytosis and production of reactive oxygen metabolites in human neutrophil granulocytes
Open this publication in new window or tab >>Glucose and insulin modulate phagocytosis and production of reactive oxygen metabolites in human neutrophil granulocytes
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neutrophil granulocytes play an important role in the host defence against invading microorganisms and constitute the frontline of defence within the innate immune system and are among the first cells to arrive at the site of inflammation. Effective phagocytosis and killing of invading pathogens by neutrophils is of significant importance for successful resistance to infectious diseases. An important complication in diabetes mellitus is an increased sensitivity to infections and increased tissue damage, leading to many secondary diseases. This may in part be explained by an impaired function of neutrophil granulocytes. Since the exact mechanisms underlying defective neutrophil function in diabetes mellitus are not fully understood, the aim of the present study was to investigate the effects of elevated glucose and insulin concentrations on phagocytosis of opsonized yeast and on production of reactive oxygen metabolites (ROS) in normal human neutrophils.

Elevated D-glucose concentrations (15-25 mM) inhibited the phagocytosis of C3bi- or IgG-opsonized yeast particles, which was neither an osmotic effect nor an effect due to reduced binding of opsonized yeast particles to the neutrophils. Inhibition of protein kinase C (PKC) by GF109203X or Go6976 could completely reverse the inhibitory effect of 25 mM D-glucose on phagocytosis. Diacylglycerol (DAG) dose-dependently inhibited phagocytosis and suboptimal inhibitory concentrations of DAG and glucose showed an additive inhibitory effect. Elevated concentrations of insulin (80-160 μU/ml) also inhibited neutrophil phagocytosis, an effect shown in part to be due to a delayed phagocytosis process. Insulin was found to increase the accumulation of cortical F-actin, without affecting the total cellular F-actin content. The PKCalpha/beta inhibitor, Go6976, abolished the insulin-mediated increase in cortical F-actin content and both Go6976 and the PKCalpha/beta/delta/epsilon-specific inhibitor GF109203X reversed the inhibitory effects of insulin on phagocytosis.

The inhibition of phagocytosis by either glucose or insulin resulted in an expected reduction of intracellular respiratory burst. However, the extracellular release of ROS during phagocytosis was increased by insulin, but inhibited by glucose. The ability of insulin to enhance ROS production was found to be F-actin dependent. Data suggests that glucose inhibited intracellular respiratory burst activation by interfering with intracellular signaling downstream of PKC activation, whereas extracellular release of ROS was inhibited by glucose upstream of PKC signaling.

Taken together these results suggest that both hyperglycemia and hyperinsulinemia inhibit complement receptor and Fc receptor-mediated phagocytosis in human neutrophils. Insulin, but not glucose, also induced an enhanced extracellular release of ROS during phagocytosis. The combination of reduced phagocytosis and alterations in ROS production may possibly explain both the increased sensitivity to infections and tissue damage seen in type 2 diabetes.

Place, publisher, year, edition, pages
Umeå: Integrativ medicinsk biologi, 2006. 49 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1005
Keyword
neutrophil granulocytes, glucose, insulin, protein kinase C, diacylglycerol, phagocytosis, respiratory burst, diabetes
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-683 (URN)91-7264-019-7 (ISBN)
Public defence
2006-02-24, BiA201, Biologihuset, Umeå universitet, Umeå, 13:00 (English)
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Supervisors
Available from: 2006-02-01 Created: 2006-02-01 Last updated: 2009-10-29Bibliographically approved

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Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14630574&query_hl=1&itool=pubmed_docsum

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Sehlin, JanoveOldenborg, Per-Arne

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