Apoptosis in rheumatoid arthritis synovium.
PDF (2.9M)
Journal: 1995/October - Journal of Clinical Investigation
ISSN: 0021-9738
Abstract:
RA synovial tissue (ST) was studied to determine if and where apoptosis occurs in situ. Genomic DNA was extracted from 5 RA and 1 osteoarthritis ST samples. Agarose gel electrophoresis demonstrated DNA ladders characteristic for apoptosis from each tissue. In situ and labeling (ISEL) was used to identify DNA strand breaks consistent with apoptosis in frozen sections. 12 RA and 4 osteoarthritis ST were studied by ISEL and all were positive, but only 2 of 4 normal tissues were positive. The primary location of apopotic cells was the synovial lining. Some sublining cells were also positive, but lymphoid aggregate staining was conspicuously absent. Immunohistochemistry and ISEL were combined and showed that the lining cells with DNA strand breaks were mainly macrophages, although some fibroblastlike cells were also labeled. Sublining cells with fragmented DNA included macrophages and fibroblasts, but T cells in lymphoid aggregates, which expressed large amounts of bcl-2, were spared. DNA strand breaks in cultured fibroblastlike synoviocytes was assessed using ISEL. Apoptosis could be induced by actinomycin D, anti-fas antibody, IL-1, and TNF-alpha but not by IFN-gamma. Fas expression was also detected on fibroblast-like synoviocytes using flow cytometry. Therefore, DNA strand breaks occur in synovium of patients with arthritis. Cytokines regulate this process, and the cytokine profile in RA (high IL-1/TNF; low IFN-gamma) along with local oxidant injury might favor induction of apoptosis.
Open in
PUBMED | DOI | PMC | Google Scholar | Wikipedia
Relations:
Content
Citations
(81)
References
(41)
Diseases
(2)
Drugs
(3)
Chemicals
(5)
Organisms
(1)
Processes
(1)
Anatomy
(5)
Affiliates
(2)
Similar articles
Articles by the same authors
Discussion board
J Clin Invest 96(3): 1631-1638
PMID: 7657832

Apoptosis in rheumatoid arthritis synovium.

Abstract

RA synovial tissue (ST) was studied to determine if and where apoptosis occurs in situ. Genomic DNA was extracted from 5 RA and 1 osteoarthritis ST samples. Agarose gel electrophoresis demonstrated DNA ladders characteristic for apoptosis from each tissue. In situ and labeling (ISEL) was used to identify DNA strand breaks consistent with apoptosis in frozen sections. 12 RA and 4 osteoarthritis ST were studied by ISEL and all were positive, but only 2 of 4 normal tissues were positive. The primary location of apopotic cells was the synovial lining. Some sublining cells were also positive, but lymphoid aggregate staining was conspicuously absent. Immunohistochemistry and ISEL were combined and showed that the lining cells with DNA strand breaks were mainly macrophages, although some fibroblastlike cells were also labeled. Sublining cells with fragmented DNA included macrophages and fibroblasts, but T cells in lymphoid aggregates, which expressed large amounts of bcl-2, were spared. DNA strand breaks in cultured fibroblastlike synoviocytes was assessed using ISEL. Apoptosis could be induced by actinomycin D, anti-fas antibody, IL-1, and TNF-alpha but not by IFN-gamma. Fas expression was also detected on fibroblast-like synoviocytes using flow cytometry. Therefore, DNA strand breaks occur in synovium of patients with arthritis. Cytokines regulate this process, and the cytokine profile in RA (high IL-1/TNF; low IFN-gamma) along with local oxidant injury might favor induction of apoptosis.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.9M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
icon of scanned page 1631
1631
icon of scanned page 1632
1632
icon of scanned page 1633
1633
icon of scanned page 1634
1634
icon of scanned page 1635
1635
icon of scanned page 1636
1636
icon of scanned page 1637
1637
icon of scanned page 1638
1638

Images in this article

Image
Image
on p.1633
Image
Image
on p.1634
Image
Image
on p.1635
Image
Image
on p.1635
Image
Image
on p.1636
Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Cotter TG, Lennon SV, Glynn JG, Martin SJ. Cell death via apoptosis and its relationship to growth, development and differentiation of both tumour and normal cells. Anticancer Res. 1990 Sep-Oct;10(5A):1153–1159. [PubMed] [Google Scholar]
  • Leist M, Gantner F, Bohlinger I, Germann PG, Tiegs G, Wendel A. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. J Immunol. 1994 Aug 15;153(4):1778–1788. [PubMed] [Google Scholar]
  • Lennon SV, Martin SJ, Cotter TG. Induction of apoptosis (programmed cell death) in tumour cell lines by widely diverging stimuli. Biochem Soc Trans. 1990 Apr;18(2):343–345. [PubMed] [Google Scholar]
  • Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. [PubMed] [Google Scholar]
  • Mangan DF, Wahl SM. Differential regulation of human monocyte programmed cell death (apoptosis) by chemotactic factors and pro-inflammatory cytokines. J Immunol. 1991 Nov 15;147(10):3408–3412. [PubMed] [Google Scholar]
  • Akbar AN, Borthwick N, Salmon M, Gombert W, Bofill M, Shamsadeen N, Pilling D, Pett S, Grundy JE, Janossy G. The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory. J Exp Med. 1993 Aug 1;178(2):427–438.[PMC free article] [PubMed] [Google Scholar]
  • D'Adamio L, Awad KM, Reinherz EL. Thymic and peripheral apoptosis of antigen-specific T cells might cooperate in establishing self tolerance. Eur J Immunol. 1993 Mar;23(3):747–753. [PubMed] [Google Scholar]
  • Owen JJ, Jenkinson EJ. Apoptosis and T-cell repertoire selection in the thymus. Ann N Y Acad Sci. 1992 Nov 21;663:305–310. [PubMed] [Google Scholar]
  • Hogquist KA, Nett MA, Unanue ER, Chaplin DD. Interleukin 1 is processed and released during apoptosis. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8485–8489.[PMC free article] [PubMed] [Google Scholar]
  • Zychlinsky A, Fitting C, Cavaillon JM, Sansonetti PJ. Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri. J Clin Invest. 1994 Sep;94(3):1328–1332.[PMC free article] [PubMed] [Google Scholar]
  • Watson ML, Rao JK, Gilkeson GS, Ruiz P, Eicher EM, Pisetsky DS, Matsuzawa A, Rochelle JM, Seldin MF. Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med. 1992 Dec 1;176(6):1645–1656.[PMC free article] [PubMed] [Google Scholar]
  • Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994 Mar 25;76(6):969–976. [PubMed] [Google Scholar]
  • Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. 1994 Mar 25;263(5154):1759–1762. [PubMed] [Google Scholar]
  • Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol. 1994 Apr 1;152(7):3685–3692. [PubMed] [Google Scholar]
  • Jones ST, Denton J, Holt PJ, Freemont AJ. Possible clearance of effete polymorphonuclear leucocytes from synovial fluid by cytophagocytic mononuclear cells: implications for pathogenesis and chronicity in inflammatory arthritis. Ann Rheum Dis. 1993 Feb;52(2):121–126.[PMC free article] [PubMed] [Google Scholar]
  • Malinin TI, Pekin TJ, Jr, Zvaifler NJ. Cytology of synovial fluid in rheumatoid arthritis. Am J Clin Pathol. 1967 Feb;47(2):203–208. [PubMed] [Google Scholar]
  • Mountz JD, Wu J, Cheng J, Zhou T. Autoimmune disease. A problem of defective apoptosis. Arthritis Rheum. 1994 Oct;37(10):1415–1420. [PubMed] [Google Scholar]
  • Alvaro-Gracia JM, Zvaifler NJ, Firestein GS. Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. J Clin Invest. 1990 Dec;86(6):1790–1798.[PMC free article] [PubMed] [Google Scholar]
  • Firestein GS, Paine MM, Boyle DL. Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial collagenase gene expression. Arthritis Rheum. 1994 Feb;37(2):193–200. [PubMed] [Google Scholar]
  • Wood KA, Dipasquale B, Youle RJ. In situ labeling of granule cells for apoptosis-associated DNA fragmentation reveals different mechanisms of cell loss in developing cerebellum. Neuron. 1993 Oct;11(4):621–632. [PubMed] [Google Scholar]
  • Wijsman JH, Jonker RR, Keijzer R, van de Velde CJ, Cornelisse CJ, van Dierendonck JH. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA. J Histochem Cytochem. 1993 Jan;41(1):7–12. [PubMed] [Google Scholar]
  • Morales-Ducret J, Wayner E, Elices MJ, Alvaro-Gracia JM, Zvaifler NJ, Firestein GS. Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. J Immunol. 1992 Aug 15;149(4):1424–1431. [PubMed] [Google Scholar]
  • Matzinger P. The JAM test. A simple assay for DNA fragmentation and cell death. J Immunol Methods. 1991 Dec 15;145(1-2):185–192. [PubMed] [Google Scholar]
  • Itoh N, Tsujimoto Y, Nagata S. Effect of bcl-2 on Fas antigen-mediated cell death. J Immunol. 1993 Jul 15;151(2):621–627. [PubMed] [Google Scholar]
  • Korsmeyer SJ. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood. 1992 Aug 15;80(4):879–886. [PubMed] [Google Scholar]
  • Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. [PubMed] [Google Scholar]
  • Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 1990 Jun;33(6):768–773. [PubMed] [Google Scholar]
  • Cronstein BN, Weissmann G. The adhesion molecules of inflammation. Arthritis Rheum. 1993 Feb;36(2):147–157. [PubMed] [Google Scholar]
  • Koch AE, Burrows JC, Haines GK, Carlos TM, Harlan JM, Leibovich SJ. Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab Invest. 1991 Mar;64(3):313–320. [PubMed] [Google Scholar]
  • Mapp PI, Revell PA. Ultrastructural characterisation of macrophages (type A cells) in the synovial lining. Rheumatol Int. 1988;8(4):171–176. [PubMed] [Google Scholar]
  • Arend WP, Smith MF, Jr, Janson RW, Joslin FG. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol. 1991 Sep 1;147(5):1530–1536. [PubMed] [Google Scholar]
  • Firestein GS, Boyle DL, Yu C, Paine MM, Whisenand TD, Zvaifler NJ, Arend WP. Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum. 1994 May;37(5):644–652. [PubMed] [Google Scholar]
  • Qu Z, Garcia CH, O'Rourke LM, Planck SR, Kohli M, Rosenbaum JT. Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organizer region staining. Arthritis Rheum. 1994 Feb;37(2):212–220. [PubMed] [Google Scholar]
  • Arends MJ, McGregor AH, Toft NJ, Brown EJ, Wyllie AH. Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability. Br J Cancer. 1993 Dec;68(6):1127–1133.[PMC free article] [PubMed] [Google Scholar]
  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. [PubMed] [Google Scholar]
  • Hermeking H, Eick D. Mediation of c-Myc-induced apoptosis by p53. Science. 1994 Sep 30;265(5181):2091–2093. [PubMed] [Google Scholar]
  • Ritchlin C, Dwyer E, Bucala R, Winchester R. Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole synovial tissue obtained from inflammatory synovitis. Scand J Immunol. 1994 Sep;40(3):292–298. [PubMed] [Google Scholar]
  • Firestein GS, Xu WD, Townsend K, Broide D, Alvaro-Gracia J, Glasebrook A, Zvaifler NJ. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med. 1988 Nov 1;168(5):1573–1586.[PMC free article] [PubMed] [Google Scholar]
  • Mangan DF, Welch GR, Wahl SM. Lipopolysaccharide, tumor necrosis factor-alpha, and IL-1 beta prevent programmed cell death (apoptosis) in human peripheral blood monocytes. J Immunol. 1991 Mar 1;146(5):1541–1546. [PubMed] [Google Scholar]
  • Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest. 1994 Oct;94(4):1621–1628.[PMC free article] [PubMed] [Google Scholar]
  • Edmonds SE, Blake DR, Morris CJ, Winyard PG. An imaginative approach to synovitis--the role of hypoxic reperfusion damage in arthritis. J Rheumatol Suppl. 1993 Apr;37:26–31. [PubMed] [Google Scholar]
University of California, San Diego Medical Center, La Jolla, California 92093, USA.
University of California, San Diego Medical Center, La Jolla, California 92093, USA.
Copyright notice
Abstract
RA synovial tissue (ST) was studied to determine if and where apoptosis occurs in situ. Genomic DNA was extracted from 5 RA and 1 osteoarthritis ST samples. Agarose gel electrophoresis demonstrated DNA ladders characteristic for apoptosis from each tissue. In situ and labeling (ISEL) was used to identify DNA strand breaks consistent with apoptosis in frozen sections. 12 RA and 4 osteoarthritis ST were studied by ISEL and all were positive, but only 2 of 4 normal tissues were positive. The primary location of apopotic cells was the synovial lining. Some sublining cells were also positive, but lymphoid aggregate staining was conspicuously absent. Immunohistochemistry and ISEL were combined and showed that the lining cells with DNA strand breaks were mainly macrophages, although some fibroblastlike cells were also labeled. Sublining cells with fragmented DNA included macrophages and fibroblasts, but T cells in lymphoid aggregates, which expressed large amounts of bcl-2, were spared. DNA strand breaks in cultured fibroblastlike synoviocytes was assessed using ISEL. Apoptosis could be induced by actinomycin D, anti-fas antibody, IL-1, and TNF-alpha but not by IFN-gamma. Fas expression was also detected on fibroblast-like synoviocytes using flow cytometry. Therefore, DNA strand breaks occur in synovium of patients with arthritis. Cytokines regulate this process, and the cytokine profile in RA (high IL-1/TNF; low IFN-gamma) along with local oxidant injury might favor induction of apoptosis.
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.