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Interferon γ-induced gene expression of the novel secretory phospholipase A2 type IID in human monocyte-derived macrophages is inhibited by lipopolysaccharide
Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
2005 (English)In: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 29, no 2-3, 108-117 p.Article in journal (Refereed) Published
Abstract [en]

Phospholipase A2 (PLA2) is a superfamily of enzymes that may play a major role in airways inflammation. We investigated the effect of interferon-γ (IFN-γ) on the gene expression of 19 different PLA2 types in human monocyte-derived macrophages and nasal epithelial cells (RPMI 2650). The cells were stimulated with IFN-γ for different lengths of time (up to 48 h), and the mRNA levels of the different PLA2 types were determined by reverse transcriptase–PCR (RT-PCR) and normalized to those of the house-keeping gene, GAPDH. It appeared that IFN-γ clearly increased the expression of secretory PLA2 IID (but not IIA) in macrophages, while both PLA2 IID and IIA were upregulated in RPMI 2650 cells. Moreover, after 18 h, the mRNA levels of cytosolic PLA2 IVA were 2–3 times higher in IFN-γ-stimulated macrophages than controls, while there was no such effect of IFN-γ in RPMI 2650 cells. Lipopolysaccharide (LPS) augmented the increased gene expression of PLA2 IVA but decreased both the basal and the IFN-γ-induced PLA2 IID mRNA expression in macrophages (but not in RPMI 2650 cells). The NF-κB inhibitor Pyrrolidine dithiocarbamate (PDTC) and the phoshatidylinositol 3-kinase (PI3K) inhibitor wortmannin were employed to get an insight into the mechanism behind these observations. Incubation of macrophages with PDTC had no effect on the LPS impairment of PLA2 IID gene expression, but inhibited the LPS mediated activation of PLA2 IVA. No significant effect was noted of PDTC on IFN-γ stimulation, while PI3K had no effect at all on any of the stimuli used. Furthermore, LPS (but not IFN-γ) increased the mRNA levels of the nuclear factor (NF)-κB inhibitors α and ξ in macrophages, but not in RPMI 2650 cells. These findings indicate that (a) the gene expression of secretory types PLA2 IID and IIA in response to IFN-γ is much dependent on cell type, and (b) the regulation of PLA2 type IID in human macrophages is clearly different from that of PLA2 type IVA. (c) PLA2 IVA is probably under control of both NF-κB and IFN-γ-responsive elements (GRE) or IFN-γ-activating sites (GAS). The possibility that PLA2 IID is involved in cytokine-mediated inflammation in the nasal mucosa is inferred, as is the potential role of PLA2 IID in the host defense against LPS-containing bacteria.

Place, publisher, year, edition, pages
2005. Vol. 29, no 2-3, 108-117 p.
Keyword [en]
IFN-?, LPS, Macrophages, Nasal mucosa, PLA2
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-45483DOI: 10.1007/s10753-006-9007-xOAI: oai:DiVA.org:liu-45483DiVA: diva2:266379
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
In thesis
1. Phospholipase A2 expression in the human nasal mucosa
Open this publication in new window or tab >>Phospholipase A2 expression in the human nasal mucosa
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Phospholipase A2 (PLA2) is a superfamily of enzymes that promote inflammation by releasing arachidonic acid for the synthesis of eicosanoids and lysophospholipid for the synthesis of platelet-activating factor (PAF). On the other hand, several members of the PLA2 family (VIIA, VIIB, VIIIA and VIIIB) are able to degrade PAF and are therefore potentially important anti-inflammatory enzymes. The precise roles of the different PLA2 enzymes in airways inflammation are not known and the gene expression of the different PLA2s in the human nasal mucosa has not previously been examined. Using reversed transcription-polymerase chain reaction (RT-PCR) techniques, this thesis investigated (i) the occurrence of mRNAs for different PLA2 types in the nasal mucosa of healthy subjects; (ii) the effects of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) on the gene expression of different PLA2s in human nasal epithelial cells (RPMI 2650); (iii) the effects of IFN-γ and lipopolysaccharide (LPS) on the gene expression of different PLA2 types in human monocyte-derived macrophages; (iv) the effects of exudates from LPS- or ß-glucan exposed macrophages on the gene expression of different PLA2 types in RPMI 2650 cells, and (v) the levels of different PLA2 mRNAs in the nasal mucosa of patients with seasonal allergic rhinitis (SAR) and healthy controls. The relative abundances of the different PLA2 transcripts in normal human nasal mucosa were found to be X ≈ IVA > IIA ≈ IIE ≈ IVB ≈ VI > IB ≈ IID ≈ III ≈ IVC ≈ VII ≈ VIB. In RPMI 2650 cells, TNF-α increased the expression of PLA2 IVA and IVC, while IFN-γ increased the expression of PLA2 IIA and IID. In macrophages, IFN-γ increased the expression of both PLA2 IID and IVA while LPS increased the expression of PLA2 IVA but decreased that of IID. Medium from macrophages exposed to LPS or ß-glucan increased the expression of PLA2 IVC in RPMI 2650 cells; this upregulation was abrogated by antibodies to TNF-α and by the nuclear factor (NF)-κB inhibitor, pyrrolidine dithiocarbamate. Notably, the mRNA levels of PLA2 VIIA (PAF acetylhydrolase I) were lower in SAR patients than controls during both the pollen season and the off-season for pollen. These findings demonstrate that a large number of PLA2 types are constitutively expressed in the normal human nasal mucosa, including the newly discovered PLA2 types IID, IIE, IIF, III, IVB, IVC, VIB, X, XIIA, and XIIB. They also demonstrate that TNF-α and IFN-γ cause increased gene expression of two novel cytosolic and secretory PLA2 types (IVC and IID, respectively) in human nasal epithelial cells, suggesting that these PLA2 types may be involved in cytokine-mediated inflammation in the nasal mucosa. Moreover, the findings indicate that both LPS- and ß-glucan-activated macrophages can induce the gene expression of PLA2 IVC in nasal epithelial cells, and that this upregulation is mediated through TNF-α and under NF-κB control. The observation that PAF acetylhydrolase mRNA expression in the nasal mucosa is lower in SAR patients than in healthy subjects points to the possibility that impaired ability to inactivate PAF might be of importance in SAR.

Place, publisher, year, edition, pages
Linköping: Linköping University, 2004. 100 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 864
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22294 (URN)1480 (Local ID)91-7373-838-7 (ISBN)1480 (Archive number)1480 (OAI)
Public defence
2004-11-11, Aulan, Hälsans hus, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-29Bibliographically approved

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Lindbom, JohnLjungman, AndersTagesson, Christer

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