title: The interferon-gamma-mediated inhibition of lipoprotein lipase gene transcription in macrophages involves casein kinase 2- and phosphoinositide-3-kinase-mediated regulation of transcription factors Sp1 and Sp3.
abstract: The mechanisms underlying transcriptional inhibition by interferon-gamma (IFN-gamma) are poorly understood despite the existence of a large number of genes that are regulated in this manner and the key role of this cytokine in inflammatory disorders such as atherosclerosis. We have previously identified a novel mechanism for transcriptional inhibition by IFN-gamma that involves a reduction in the binding of transcription factors Sp1 and Sp3 to regulatory sequences in the lipoprotein lipase (LPL) gene. In the present study, we have investigated the signalling pathways that impact on the IFN-gamma-mediated regulation of Sp1/Sp3 binding and LPL gene transcription in macrophages. The IFN-gamma-mediated inhibition of LPL promoter activity was prevented by expression of dominant negative forms of casein kinase 2 (CK2) and protein kinase B (PKB), a key downstream component of the phosphoinositide-3-kinase (PI3K) pathway. IFN-gamma activated both the catalytic subunits of CK2 without affecting their expression. CK2 interacted with both Sp1 and Sp3 and this association was increased by IFN-gamma. Electrophoretic mobility shift assays showed that a CK2-mediated phosphorylation of either cellular extracts or recombinant Sp1 reduced binding to the regulatory region in the LPL gene. The action of PKB was potentially mediated through mammalian target for rapamycin proteins. Taken together, these results suggest a key role for CK2 and PI3K signalling pathways in the IFN-gamma-mediated inhibition of macrophage LPL gene transcription through the regulation of Sp1/Sp3 binding.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Harris
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Harvey
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: Dipak P
authors.initials: DP
authors.lastname: Ramji
mesh_terms: D047390:Casein Kinase II / Q000276:immunology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D051703:Sp Transcription Factors / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D051703:Sp Transcription Factors; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D047390:Casein Kinase II; D008071:Lipoprotein Lipase
references.citation: Int J Colorectal Dis. 2007 Jun;22(6):601-9
references.pmid: 17009010
references.citation: Nucleic Acids Res. 2005 Mar 08;33(5):1423-34
references.pmid: 15755745
references.citation: Cell Microbiol. 2008 Sep;10(9):1787-800
references.pmid: 18452580
references.citation: Am J Pathol. 2000 Dec;157(6):1819-24
references.pmid: 11106554
references.citation: Cardiovasc Res. 2002 Aug 1;55(2):261-9
references.pmid: 12123765
references.citation: J Biol Chem. 2003 May 16;278(20):17741-51
references.pmid: 12609974
references.citation: J Clin Invest. 2001 Jun;107(11):1451-8
references.pmid: 11390427
references.citation: Pain. 2005 May;115(1-2):182-90
references.pmid: 15836981
references.citation: Biochem J. 1998 Oct 1;335 ( Pt 1):1-13
references.pmid: 9742206
references.citation: Annu Rev Immunol. 1997;15:749-95
references.pmid: 9143706
references.citation: Circ Res. 2007 Aug 17;101(4):348-56
references.pmid: 17495225
references.citation: Mol Cell Biochem. 2007 Aug;302(1-2):9-18
references.pmid: 17286201
references.citation: J Mol Med (Berl). 2008 Aug;86(8):887-97
references.pmid: 18437331
references.citation: J Mol Med (Berl). 2002 Dec;80(12):753-69
references.pmid: 12483461
references.citation: Circ Res. 2004 Oct 1;95(7):684-91
references.pmid: 15345653
references.citation: Oncogene. 2001 Apr 12;20(16):2010-22
references.pmid: 11360185
references.citation: Cytokine. 1998 Jan;10(1):38-48
references.pmid: 9505144
references.citation: Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):806-12
references.pmid: 17255531
references.citation: Cytokine. 1996 Jul;8(7):525-33
references.pmid: 8891433
references.citation: Proc Natl Acad Sci U S A. 2007 May 8;104(19):8077-82
references.pmid: 17483449
references.citation: Biochem Soc Trans. 1998 Feb;26(1):S12
references.pmid: 10909770
references.citation: Cell Signal. 2006 Apr;18(4):508-18
references.pmid: 16157472
references.citation: Int J Oncol. 2003 Jun;22(6):1263-70
references.pmid: 12738992
references.citation: J Biol Chem. 2004 May 14;279(20):21421-30
references.pmid: 14993215
references.citation: Metabolism. 1998 May;47(5):555-9
references.pmid: 9591746
references.citation: Int J Biochem Cell Biol. 2006 Jan;38(1):12-6
references.pmid: 16140560
references.citation: J Biol Chem. 2002 Mar 29;277(13):11097-106
references.pmid: 11796707
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4808-13
references.pmid: 18339807
references.citation: Trends Immunol. 2002 Feb;23(2):96-101
references.pmid: 11929133
references.citation: J Biol Chem. 1997 May 23;272(21):13489-95
references.pmid: 9153193
references.citation: Cytokine. 1999 Jul;11(7):463-8
references.pmid: 10419646
references.citation: Am J Physiol Cell Physiol. 2006 Nov;291(5):C887-96
references.pmid: 16760259
references.citation: J Exp Med. 2001 Oct 15;194(8):1123-40
references.pmid: 11602641
references.citation: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7736-41
references.pmid: 15897466
references.citation: Oncogene. 2002 Aug 8;21(34):5280-8
references.pmid: 12149649
references.citation: Drug Discov Today. 2007 Feb;12(3-4):112-24
references.pmid: 17275731
references.citation: Cardiovasc Res. 2005 Jul 1;67(1):11-20
references.pmid: 15907820
references.citation: Oncogene. 2005 Mar 17;24(12):2050-8
references.pmid: 15688023