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Sialic Acid Dependent and Independent Effects of alpha 1-Acid Glycoprotein (AGP) on Human Platelets
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of health and environment. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
2008 (English)In: 2008 Meeting of the Society for Glycobiology, 2008, Vol. 18, no 11, 990-990 p.Conference paper, Published paper (Other academic)
Abstract [en]

Objective: We have recently shown that terminal sialic acid residues are essential for α1-acidglycoprotein (AGP)-induced Ca2+ mobilization in neutrophils. The aim of the present studywas to establish the importance of sialic acid-residues on AGP in modulating humanneutrophil functions, with emphasis on the generation of reactive oxygen species (ROS).Material and methods: ROS were measured by luminol-enhanced chemiluminescence inisolated human neutrophils.

Results: We found that AGP did not provoke ROS generation in resting or L-selectin presensitizedneutrophils. Moreover, AGP did not affect the N-formyl-methionyl-leucylphenylalanine(fMLP)-induced ROS generation but it slightly suppressed opsonized zymosaninducedresponses. However, when the neutrophils were pre-stimulated with fMLP, thefollowing addition of AGP provoked a marked ROS response. Dose-response studies and timestudies revealed that the ROS generating capacity of AGP was maximal at a concentration of0.05 mg/ml and when given 3-10 min after addition of fMLP. A desialylated form of AGP orpre-treatment of neutrophils with 3’- and 6’-sialyllactose caused a substantial lower ROSresponse in neutrophils pre-stimulated with fMLP.

Conclusions: Our data show that AGP can stimulate a second ROS response in fMLP preactivatedneutrophils and that terminal sialic acid residues on AGP play a crucial role in thisregard.

Place, publisher, year, edition, pages
2008. Vol. 18, no 11, 990-990 p.
Keyword [en]
α1-acid glycoprotein, neutrophils, reactive oxygen species, sialic acid
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-16353OAI: oai:DiVA.org:liu-16353DiVA: diva2:133970
Available from: 2009-01-16 Created: 2009-01-16 Last updated: 2009-09-09
In thesis
1. α1-acid glycoprotein modulates the function of human neutrophils and platelets
Open this publication in new window or tab >>α1-acid glycoprotein modulates the function of human neutrophils and platelets
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The acute-phase protein α1-acid glycoprotein (AGP; orosomucoid) was initially identified andcharacterised in the 1950s. The normal plasma concentration is around 0.5-1 mg/ml butduring inflammation the concentration increase several fold and the carbohydrate compositionof the protein changes. AGP is a highly glycosylated protein with 45 % of the molecularweight consisting of glycans. These glycans are believed to be of importance for the functionof the protein. However, the precise physiological role of AGP is still unclear.

The present thesis reveals that AGP at physiological concentration induce calcium elevationin human neutrophils and platelets. In neutrophils this response was enhanced several fold ifsurface L-selectin was pre-engaged. Our results showed that this L-selectin-mediatedamplification was abolished if the neutrophils were pre-treated with Src or phosphoinositide3-kinase (PI3K) inhibitors. AGP alone did not induce production of reactive oxygen species(ROS) in neutrophils. However, if the neutrophils were activated by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) a subsequent addition of AGP caused aprominent ROS response. Moreover, both the calcium rise and the ROS response weredepending on sialic acid residues on AGP. In the case of calcium elevation we defined thereceptor as sialic-acid-binding immunoglobulin-like lectin (Siglec)-5 on the neutrophil.

In platelets, AGP induced a Rho-kinase dependent phosphorylation of myosin phosphatasetarget subunit-1 (MYPT1) and a minor calcium response. This resulted in a prominent plateletshape change (i.e. spherical shape and granule centralization) recorded as change in lighttransmission and by differential interference contrast (DIC) microscopy. The shape changecaused by AGP was strongly suppressed by inhibition of Rho-kinase and abolished by Rhokinaseinhibition combined with chelation of intracellular calcium. No other manifestations ofplatelet activation like aggregation or secretion were registered. Opposite to neutrophils theeffect of AGP on platelets was not mediated by an interaction between sialic acid and siglecmolecules. However, the results indicated that AGP may bind to a collagen/thrombospondin-1surface receptor. Endogenous inhibitors like nitric oxide (NO) and adenosine abolished theAGP-induced platelet shape change. The antagonizing action of NO on shape change causedby AGP was long acting. In comparison, other aspects of agonist-induced platelet activation(e.g. intracellular calcium elevations) are only transiently suppressed by NO. This indicatesthat endothelium-derived NO may play a crucial role to counter balance the effect of AGP in vivo.

Take together the results in this thesis reveal that AGP can initiate intracellular signalling andmodulate functional responses in neutrophils and platelets.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 65 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1135
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20476 (URN)978-91-7393-614-9 (ISBN)
Public defence
2009-09-04, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-09-09 Created: 2009-09-09 Last updated: 2012-02-03Bibliographically approved

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Gunnarsson, PeterLevander, LouisePåhlsson, PeterGrenegård, Magnus

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