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Alpha1-acid glycoprotein is a carrier of hydroxyeicosatetraenoic acids – role in calcium mobilization ofpolymorphonuclear granulocytes
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have previously shown that α1-acid glycoprotein (AGP) induces rises incytosolic calcium concentration, [Ca2+]i, in human polymorphonuclear granulocytes(PMN) and that this effect is enhanced by prior pre-sensitization of PMN with theanti L-selectin antibody DREG-56. AGP is a known carrier of several lipophilicsubstances. This study was designed to determine whether lipids bound to AGP areinvolved in the induction of [Ca2+]i mobilization in PMN. We found that delipidatedAGP elicited a smaller rise in [Ca2+]i in DREG-56 pretreated PMN compared tonative AGP and that lipids extracted from AGP provoked an increase in [Ca2+]i thatwas potentiated by L-selectin pre-engagement with DREG-56. Similarly to whatwas previously found for AGP, the increase in [Ca2+]i produced by the AGP lipidextract involved activation of src-tyrosine kinases and PI3-kinases. The AGP lipidextract was analyzed by high-performance thin layer chromatography. Individualbands were extracted from the plate and their Ca2+ mobilizing activity wasanalyzed. One band contained activity and was further analyzed by electro-spraytandem mass spectrometry. The active band contained a mixture of hydroxyeicosatetraenoic acids (HETEs) with 12-HETE being one of the major components.Pharmacological studies indicated that the AGP lipid extract acted through theleukotriene B4-receptor type II, BLT2. This study supports the hypothesis that someof the immunomodulatory properties that have been attributed to AGP may beconnected to lipids carried by this plasma protein.

Keyword [en]
alpha1-acid glycoprotein, hydroxy eicosatetraenoic acids, BLT2, cytosolic calcium, polymorphonuclear leukocyte
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-20267OAI: oai:DiVA.org:liu-20267DiVA: diva2:233559
Available from: 2009-09-01 Created: 2009-09-01 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Effects of α1‐acid glycoprotein onpolymorphonuclear leukocytes ‐involvement of cell surface receptors
Open this publication in new window or tab >>Effects of α1‐acid glycoprotein onpolymorphonuclear leukocytes ‐involvement of cell surface receptors
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alpha1‐acid glycoprotein (AGP) is a highly glycosylated lipid‐binding acute‐phaseprotein. Although the exact mechanisms are unknown, several studies havesuggested that AGP may regulate the function of neutrophils and hence modulateinflammatory responses. The general aim of this thesis was to investigate if AGP isable to mediate intracellular signalling in neutrophils through binding to specificreceptors.

Measurements of intracellular calcium concentration showed that AGP elicited asmall rise in [Ca2+]i in neutrophils that was markedly enhanced by pre‐treatmentwith anti‐L‐selectin antibodies. In contrast, desialylation of AGP reduced the Ca2+mobilizing capacity significantly. The AGP‐induced Ca2+ signal was mediatedthrough Src tyrosine kinases, PLC and PI3K which suggests involvement of cellsurface receptors. Indeed, AGP was shown to bind to, and mediate Ca2+ signallingthrough, sialic acid binding immunoglobulin‐like lectin (Siglec)‐5 and/or ‐14.Increased fucosylation of AGP is common during acute‐phase reactions. We showthat hyperfucosylated AGP has a diminished Ca2+ signalling capacity compared tonormally fucosylated AGP. This could be due to a reduced capacity of AGP tointeract with Siglec‐5/‐14 since it is known that the presence of fucose residues onsialylated glycans has a negative effect on Siglec‐5/‐14 affinity. AGP was alsodemonstrated to bind to the neutrophil proteins S100A8 and S100A9. In additionwe show that AGP‐bound hydroxyeicasotetraenoic acids (HETEs) induce increasesin [Ca2+]i in neutrophils through binding to the leukotriene B4 receptor BLT2. Wepropose a two‐step binding model where AGP binds to Siglec‐5/‐14 on L‐selectinactivated neutrophils. This may orient AGP in a way that assists an interactionbetween AGP and the neutrophil membrane which favours transfer of AGP‐boundHETEs to the BLT2 receptor.

In conclusion, these data gives new insights regarding how AGP interacts with andmediates signalling in human neutrophils and supports the view of AGP as beingan acute phase reactant with immunomodulatory properties.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 61 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1139
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20271 (URN)978‐91‐7393‐574‐6 (ISBN)
Public defence
2009-08-28, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-09-01 Created: 2009-09-01 Last updated: 2009-09-01Bibliographically approved

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Levander, LouiseGunnarsson, PeterGrenegård, MagnusPåhlsson, Peter

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