title: Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation.
abstract: During immune-complex-mediated arthritis (ICA), severe cartilage destruction is mediated by Fcgamma receptors (FcgammaRs) (mainly FcgammaRI), cytokines (e.g. IL-1), and enzymes (matrix metalloproteinases (MMPs)). IL-13, a T helper 2 (Th2) cytokine abundantly found in synovial fluid of patients with rheumatoid arthritis, has been shown to reduce joint inflammation and bone destruction during experimental arthritis. However, the effect on severe cartilage destruction has not been studied in detail. We have now investigated the role of IL-13 in chondrocyte death and MMP-mediated cartilage damage during ICA. IL-13 was locally overexpressed in knee joints after injection of an adenovirus encoding IL-13 (AxCAhIL-13), 1 day before the onset of arthritis; injection of AxCANI (an empty adenoviral construct) was used as a control. IL-13 significantly increased the amount of inflammatory cells in the synovial lining and the joint cavity, by 30% to 60% at day 3 after the onset of ICA. Despite the enhanced inflammatory response, chondrocyte death was diminished by two-thirds at days 3 and 7. The mRNA level of FcgammaRI, a receptor shown to be crucial in the induction of chondrocyte death, was significantly down-regulated in synovium. Furthermore, MMP-mediated cartilage damage, measured as neoepitope (VDIPEN) expression using immunolocalization, was halved. In contrast, mRNA levels of MMP-3, -9, -12, and -13 were significantly higher and IL-1 protein, which induces production of latent MMPs, was increased fivefold by IL-13. This study demonstrates that IL-13 overexpression during ICA diminished both chondrocyte death and MMP-mediated VDIPEN expression, even though joint inflammation was enhanced.
authors.affiliation: Department of Experimental Rheumatology and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. k.nabbe@reuma.umcn.nl
authors.forename: Karin C A M
authors.initials: KC
authors.lastname: Nabbe
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.forename: Astrid E M
authors.initials: AE
authors.lastname: Holthuysen
authors.forename: Annet W
authors.initials: AW
authors.lastname: Sloëtjes
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002358:Cartilage, Articular / Q000473:pathology*; D016923:Cell Death; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D019902:Chondrocytes / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D007105:Immune Complex Diseases / Q000473:pathology / Q000517:prevention & control*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D007719:Knee Joint; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000096:biosynthesis* / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D018925:Chemokines; C485701:Fcgr1 protein, mouse; D007375:Interleukin-1; D018793:Interleukin-13; D009842:Oligopeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C093378:peptide VDIPEN; D020782:Matrix Metalloproteinases
references.citation: J Clin Invest. 2002 Aug;110(4):463-74
references.pmid: 12189240
references.citation: J Immunol. 2002 Oct 15;169(8):4298-306
references.pmid: 12370361
references.citation: Am J Pathol. 2003 Aug;163(2):743-52
references.pmid: 12875993
references.citation: J Immunol. 1991 Dec 15;147(12):4185-91
references.pmid: 1753095
references.citation: J Biol Chem. 2002 Aug 16;277(33):30271-82
references.pmid: 12058032
references.citation: Res Immunol. 1997 Sep;148(7):466-74
references.pmid: 9498008
references.citation: Arthritis Rheum. 1996 Oct;39(10):1693-702
references.pmid: 8843860
references.citation: J Clin Invest. 1997 Sep 15;100(6):1416-24
references.pmid: 9294107
references.citation: J Biol Chem. 1995 Mar 10;270(10):5084-8
references.pmid: 7890616
references.citation: Arthritis Res. 2000;2(6):489-503
references.pmid: 11056679
references.citation: J Clin Invest. 1995 May;95(5):2178-86
references.pmid: 7537757
references.citation: Chest. 2003 Mar;123(3 Suppl):339S-45S
references.pmid: 12628967
references.citation: Arthritis Rheum. 1996 Sep;39(9):1545-55
references.pmid: 8814067
references.citation: J Clin Invest. 1996 Dec 1;98(11):2572-9
references.pmid: 8958220
references.citation: J Immunol. 1999 Oct 15;163(8):4546-56
references.pmid: 10510398
references.citation: Immunity. 2001 Jun;14(6):693-704
references.pmid: 11420040
references.citation: J Cell Physiol. 2003 Dec;197(3):379-87
references.pmid: 14566967
references.citation: Hum Gene Ther. 2002 Feb 10;13(3):381-93
references.pmid: 11860705
references.citation: Blood. 2001 Dec 1;98(12):3421-8
references.pmid: 11719383
references.citation: Arthritis Rheum. 1999 Oct;42(10):2074-84
references.pmid: 10524678
references.citation: Ann Rheum Dis. 2001 Feb;60(2):150-7
references.pmid: 11156549
references.citation: Eur J Immunol. 2002 Oct;32(10):2915-22
references.pmid: 12355445
references.citation: J Immunol. 2002 Mar 15;168(6):2953-62
references.pmid: 11884467
references.citation: Am J Respir Cell Mol Biol. 2004 Jan;30(1):84-90
references.pmid: 12842850
references.citation: Eur Cytokine Netw. 1998 Dec;9(4):633-8
references.pmid: 9889407
references.citation: J Histochem Cytochem. 2000 Aug;48(8):1033-42
references.pmid: 10898798
references.citation: Biol Chem. 1997 Mar-Apr;378(3-4):151-60
references.pmid: 9165065
references.citation: Eur Cytokine Netw. 1997 Dec;8(4):333-44
references.pmid: 9459612
references.citation: Arthritis Rheum. 1999 Jun;42(6):1128-39
references.pmid: 10366105
references.citation: Cell Immunol. 2003 Aug;224(2):65-73
references.pmid: 14609572
references.citation: J Neuroimmunol. 2001 Feb 1;113(1):49-62
references.pmid: 11137576
references.citation: Clin Exp Immunol. 1999 Aug;117(2):376-82
references.pmid: 10444273
references.citation: J Immunol. 1993 Dec 1;151(11):6370-81
references.pmid: 7902377
references.citation: Ann N Y Acad Sci. 1999 Jun 30;878:120-9
references.pmid: 10415724
references.citation: J Immunol. 2001 Apr 15;166(8):5193-200
references.pmid: 11290803
references.citation: Rheumatol Int. 2004 Jul;24(4):207-11
references.pmid: 12898179
references.citation: Arthritis Rheum. 2003 Jan;48(1):255-65
references.pmid: 12528127
references.citation: Osteoarthritis Cartilage. 2002 Mar;10(3):234-43
references.pmid: 11869085
references.citation: J Immunol. 1996 Jan 1;156(1):1-4
references.pmid: 8598448
references.citation: Arthritis Rheum. 1997 Dec;40(12):2105-15
references.pmid: 9416846
references.citation: J Immunol. 2001 Jan 15;166(2):1214-22
references.pmid: 11145704
references.citation: J Rheumatol. 2002 Mar;29(3):454-61
references.pmid: 11908556
references.citation: Arthritis Rheum. 1995 Feb;38(2):164-72
references.pmid: 7848306