title: The HIV matrix protein p17 promotes the activation of human hepatic stellate cells through interactions with CXCR2 and Syndecan-2.
abstract: BACKGROUND
  The human immunodeficiency virus type 1 (HIV-1) p17 is a matrix protein involved in virus life's cycle. CXCR2 and Syndecan-2, the two major coreceptors for the p17 protein, are expressed in hepatic stellate cells (HSCs), a key cell type involved in matrix deposition in liver fibrotic disorders.
  
  
  OBJECTIVE
  In this report we have investigated the in vitro impact of p17 on HSCs transdifferentiation and function and underlying signaling pathways involved in these processes.
  
  
  METHODS
  LX-2 cells, a human HSC line, and primary HSC were challenged with p17 and expressions of fibrogenic markers and of p17 receptors were assessed by qRT-PCR and Western blot. Downstream intracellular signaling pathways were evaluated with qRT-PCR and Western blot as well as after pre-treatment with specific pathway inhibitors.
  
  
  RESULTS
  Exposure of LX2 cells to p17 increases their contractile force, reshapes the cytoskeleton fibers and upregulates the expression of transdifferentiation markers including αSMA, COL1α1 and endothelin-1 through the activation of Jak/STAT and Rho signaling pathways. These effects are lost in HSCs pre-incubated with a serum from HIV positive person who underwent a vaccination with a p17 peptide. Confocal laser microscopy studies demonstrates that CXCR2 and syndecan-2 co-associate at the plasma membrane after exposure to p17. Immunostaining of HIV/HCV liver biopsies from co-infected patients reveals that the progression of liver fibrosis correlates with a reduced expression of CXCR2.
  
  
  CONCLUSIONS
  The HIV matrix protein p17 is pro-fibrogenic through its interactions both with CXCR2 and syndecan-2 on activated HSCs.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Perugia, Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Francisci
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Schiaroli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Perugia, Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: Department of Experimental and Clinical Medicine, University of Perugia, Perugia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, Section of Anatomic Pathology and Histology, University of Perugia, Perugia, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sidoni
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, Section of Anatomic Pathology and Histology, University of Perugia, Perugia, Italy.
authors.forename: Rachele Del
authors.initials: RD
authors.lastname: Sordo
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, Section of Anatomic Pathology and Histology, University of Perugia, Perugia, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Ferri
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Lunghi
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Baldelli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000276:immunology; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D018450:Disease Progression; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015488:HIV Antigens / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D021381:Protein Transport; D053700:Receptors, Interleukin-8 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053669:Syndecan-2 / Q000378:metabolism*; D014611:Vaccination; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism* / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000914:Antibodies, Viral; D024042:Collagen Type I; D019332:Endothelin-1; D015488:HIV Antigens; D053700:Receptors, Interleukin-8; D023063:Receptors, Interleukin-8B; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; D053669:Syndecan-2; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins
references.citation: Biochem J. 2000 Jun 1;348 Pt 2:241-55
references.pmid: 10816416
references.citation: Vaccine. 2014 Feb 19;32(9):1072-8
references.pmid: 24456624
references.citation: Virology. 2007 Dec 5;369(1):47-54
references.pmid: 17706261
references.citation: Arch Intern Med. 2006 Aug 14-28;166(15):1632-41
references.pmid: 16908797
references.citation: Biochem J. 1992 Jul 15;285 ( Pt 2):367-71
references.pmid: 1379043
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14580-5
references.pmid: 22904195
references.citation: Blood. 2012 Mar 8;119(10):2274-83
references.pmid: 22262769
references.citation: J Biol Chem. 2001 Jan 5;276(1):341-7
references.pmid: 11035001
references.citation: J Infect Dis. 2008 May 15;197 Suppl 3:S279-93
references.pmid: 18447614
references.citation: Hepatology. 1996 Jul;24(1):233-40
references.pmid: 8707268
references.citation: J Clin Invest. 2001 Jul;108(2):169-73
references.pmid: 11457867
references.citation: Gut. 2002 Apr;50(4):571-81
references.pmid: 11889082
references.citation: Biochem Biophys Res Commun. 1999 Dec 20;266(2):296-300
references.pmid: 10600496
references.citation: PLoS One. 2013 Dec 31;8(12):e85737
references.pmid: 24392029
references.citation: J Biol Chem. 1996 Aug 23;271(34):20246-9
references.pmid: 8702756
references.citation: Gastroenterology. 2008 May;134(6):1655-69
references.pmid: 18471545
references.citation: Gut. 2010 Apr;59(4):428-9
references.pmid: 20332514
references.citation: Cell Tissue Res. 2010 Apr;340(1):71-9
references.pmid: 20217138
references.citation: Curr HIV Res. 2007 Sep;5(5):490-8
references.pmid: 17896969
references.citation: Gut. 2006 Sep;55(9):1276-89
references.pmid: 16484507
references.citation: Acta Histochem Cytochem. 2013 Oct 30;46(5):137-43
references.pmid: 24194627
references.citation: Oncogene. 2006 Apr 20;25(17):2520-30
references.pmid: 16474852
references.citation: J Cell Sci. 2007 Oct 15;120(Pt 20):3491-9
references.pmid: 17928305
references.citation: FASEB J. 1991 Mar 1;5(3):271-7
references.pmid: 2001786
references.citation: Immunity. 2003 Jan;18(1):27-39
references.pmid: 12530973
references.citation: World J Gastroenterol. 2010 Oct 28;16(40):5047-56
references.pmid: 20976841
references.citation: J Virol. 2004 Jun;78(12):6567-84
references.pmid: 15163749
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19464-9
references.pmid: 18040049
references.citation: J Biol Chem. 2005 Nov 25;280(47):39493-504
references.pmid: 16157597
references.citation: J Hepatol. 2010 May;52(5):635-43
references.pmid: 20347177
references.citation: PLoS One. 2012;7(3):e33659
references.pmid: 22479424
references.citation: PLoS One. 2012;7(4):e35924
references.pmid: 22558273
references.citation: J Virol. 2007 Jun;81(12):6434-45
references.pmid: 17392361
references.citation: PLoS One. 2009;4(2):e4623
references.pmid: 19247452
references.citation: J Pharmacol Exp Ther. 2011 Jun;337(3):628-35
references.pmid: 21383021
references.citation: J Biol Chem. 2011 Jun 3;286(22):19541-8
references.pmid: 21482826
references.citation: PLoS One. 2010 Nov 11;5(11):e13955
references.pmid: 21085652
references.citation: Mol Pharmacol. 2003 Oct;64(4):923-31
references.pmid: 14500749
references.citation: Gut. 2010 Apr;59(4):513-20
references.pmid: 19736361
references.citation: J Virol. 2006 Mar;80(5):2405-17
references.pmid: 16474147