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IFN-gamma-induced upregulation of Fc gamma-receptor-I during activation of monocytic cells requires the PKR and NF kappa B pathways
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2007 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 44, no 4, 615-624 p.Article in journal (Refereed) Published
Abstract [en]

Interferon (IFN)-gamma is a potent activator of macrophages, increasing the cells capacity to perform specific functions during inflammation and immune response.

In this report we use IFN-gamma-induced upregulation of the high affinity receptor for IgG (Fc gamma RI/CD64) in the human monocytic cell line U-937 as a model for monocytic activation.

We show that upregulation of Fc gamma RI is dependent on signals mediated by the dsRNA-dependent kinase PKR, and the transcription factor NF kappa B. silencing of PKR expression by siRNA or inhibition of PKR by 2-aminopurine (2-AP) potently blocks the IFN-gamma-induced transcriptional activation of the Fc gamma RI promoter. We find that the serine 727 phosphorylation of Stat1, required for full IFN-gamma-induced Fc gamma RI promoter activity, is dependent on PKR. We further show that IFN-gamma induction of Fc gamma RI upregulation is dependent on the NF kappa B pathway, as evidenced by inhibition of NF kappa B using a phosphorylation defective I kappa B alpha (S32A/S36A) mutant, or inhibiting the IKB-kinase (IKK) by treatment with BMS345541. Our results suggest that IFN-gamma-induced increase of Fc gamma RI expression requires the integration of two signalling events: PKR-dependent Stat1 serine 727 phosphorylation, and activation of NF kappa B.

Place, publisher, year, edition, pages
2007. Vol. 44, no 4, 615-624 p.
Keyword [en]
inflammation, immune response, transcription, signal transduction, Fc gamma-receptor, PKR, Stat1, NF kappa B, interferon, U-937, U937
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-10557DOI: 10.1016/j.molimm.2006.01.013ISI: 000241460900038PubMedID: 16516295OAI: oai:DiVA.org:uu-10557DiVA: diva2:38325
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Signal Transduction in Malignant Cells – Transformation, Activation and Differentiation
Open this publication in new window or tab >>Signal Transduction in Malignant Cells – Transformation, Activation and Differentiation
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

All aspects of cell life are regulated by signal transduction mechanisms. This thesis describes the regulatory roles of a few key signal transduction molecules involved in three major biological responses. The studied pathways include platelet derived growth factor (PDGF)-BB induced transformation of murine fibroblasts, interferon (IFN)-γ stimulated monocyte activation and all-trans retinoic acid (ATRA) induced myeloid differentiation.

We found that intact phosphoinositide 3OH-kinase (PI3K) activity is essential in the signaling pathway that leads to the morphological alterations and migration pattern characteristic of PDGF-BB transformed NIH/sis and NIH/COL1A1 fibroblasts. Furthermore, our data indicated that the small Rho-GTPase, Rac1 is the predominant mediator of these signals downstream of PI3K.

The study of the IFN-γ induced activation of monocytic U-937 cells showed that upregulation of the high affinity receptor for IgG (FcγRI) is dependent on the coordination of several regulatory events: the PKR-mediated serine 727 phosphorylation of Stat1, the expression of the hematopoietic lineage specific transcription factor PU.I, and the activation of the NFκB pathway.

ATRA-induced differentiation and cell cycle arrest are impaired in U-937 sublines expressing phosphorylation deficient Stat1 (Stat1Y701F and Stat1S727A). The findings in paper III indicated that the expression pattern of the myeloid specific transcription factors Stat2, ICSBP and c/EBPε was altered in the sublines and that intact Stat1 activation is critical for maintaining the balance of the transcriptional network during ATRA induced terminal differentiation.

Finally, ATRA-induced differentiation and growth arrest were blocked by treatment with the IKKα/β inhibitor BMS345541 or by ectopic expression of the NFκB super repressor IκBα (S32A/S36A). The fact that IκB(AA) sublines differentiated normally in response to vitamin D3, showed that NFκB inhibition specifically affected ATRA induced responses. Notably we suggest that the activity of the NFκB pathway may interfere with the differentiation process via a direct effect on the RAR/RXR mediated transcription.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 107
Keyword
Molecular medicine, transformation, PDGF, PI3K, Rho-GTPase, U-937, FcγRI, macrophage, Stat1, PKR, NFκB, ATRA, differentiation, Molekylärmedicin
National Category
Medical Genetics
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-6346 (URN)91-554-6465-3 (ISBN)
Public defence
2006-03-10, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarsköldsväg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-02-10 Created: 2006-02-10 Last updated: 2013-09-04Bibliographically approved

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Dimberg, AnnaNilsson, KennethÖberg, Fredrik

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