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Journal of Clinical Immunology

Erschienen in:

01.11.2007

Carboxypeptidase D: A Novel TGF-β Target Gene Dysregulated in Patients with Lupus Erythematosus

verfasst von: Norman-Philipp Hoff, Daniel Degrandi, Ulrich Hengge, Klaus Pfeffer, Jens Ulrich Wurthner

Erschienen in: Journal of Clinical Immunology | Ausgabe 6/2007

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Abstract

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that mainly acts as an inhibitor of immune functions. A lack of functional TGF-β leads to autoimmune disease in animal models and dysregulated TGF-β signaling is implicated in human autoimmune diseases. To define target genes that play a part in the inhibitory role of TGF-β in the immune system, we have identified genes stimulated by TGF-β in macrophages by gene-chip analysis. One of the TGF-β regulated genes is carboxypeptidase D (CpD), a 180-kDa type I membrane protein. We have demonstrated that CpD is regulated by TGF-β in various cell types of both, murine and human origin and, interestingly, is significantly downregulated in CD14 positive cells isolated from patients with lupus erythematosus (LE). Moreover, we show that downregulation of CpD leads to downmodulation of TGF-β itself, suggesting a role for CpD in a positive feedback loop, providing further evidence for a role of this enzyme in LE. To our knowledge, this is the first report that demonstrates carboxypeptidase D as a TGF-β target gene that is implicated in the pathogenesis of LE.

Roberts AB, Sporn MB. The transforming growth factors-b. In: Sporn MB, Roberts AB, editors. Handbook of experimental pharmacology. Peptide growth factors and their receptors. Berlin: Springer; 1990. p. 419–72.

Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000;2:309.

de Caestecker MP, Piek E, Roberts AB. Role of transforming growth factor-beta signaling in cancer. J Natl Cancer Inst 2000;17:402.

Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med 2000;342(18):1350–8.PubMedCrossRef

Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J 2004;18(7):816–27.PubMedCrossRef

Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 2004;35(2):83–92.PubMedCrossRef

Chen YG, Meng AM. Negative regulation of TGF-beta signaling in development. Cell Res 2004;14(6):441–9.PubMedCrossRef

Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992;359(6397):693–9.PubMedCrossRef

Hahm KB, Im YH, Parks TW, Park SH, Markowitz S, Jung HY et al. Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut 2001;49(2):190–8.PubMedCrossRef

10.

Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest 2001;108(4):601–9.PubMedCrossRef

11.

Fiocchi C. TGF-beta/Smad signaling defects in inflammatory bowel disease: mechanisms and possible novel therapies for chronic inflammation. J Clin Invest 2001;108(4):523–6.PubMedCrossRef

12.

Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol 1998;16:137–61, 137–61.PubMedCrossRef

13.

Mokhtarian F, Shi Y, Shirazian D, Morgante L, Miller A, Grob D. Defective production of anti-inflammatory cytokine, TGF-beta by T cell lines of patients with active multiple sclerosis. J Immunol 1994;152:6003–10.PubMed

14.

Ohtsuka K, Gray JD, Stimmler MM, Toro B, Horwitz DA. Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol 1998;160(5):2539–45.PubMed

15.

Losy J, Michalowska-Wender G. In vivo effect of interferon-beta 1a on interleukin-12 and TGF-beta(1) cytokines in patients with relapsing-remitting multiple sclerosis. Acta Neurol Scand 2002;106(1):44–6.PubMedCrossRef

16.

Kim SY, Han SW, Kim GW, Lee JM, Kang YM. TGF-beta1 polymorphism determines the progression of joint damage in rheumatoid arthritis. Scand J Rheumatol 2004;33(6):389–94.PubMedCrossRef

17.

Flanders KC, Burmester JK. Medical applications of transforming growth factor-beta. Clin Med Res 2003;1(1):13–20.PubMedCrossRef

18.

Bach JF, Bendelac A, Brenner MB, Cantor H, De Libero G, Kronenberg M et al. The role of innate immunity in autoimmunity. J Exp Med 2004;200(12):1527–31.PubMedCrossRef

19.

Carroll M. Innate immunity in the etiopathology of autoimmunity. Nat Immunol 2001;2(12):1089–90.PubMedCrossRef

20.

Vollmer J, Tluk S, Schmitz C, Hamm S, Jurk M, Forsbach A et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J Exp Med 2005;202(11):1575–85.PubMedCrossRef

21.

Li C, Wong WH. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci U S A 2001;98(1):31–6.PubMedCrossRef

22.

Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 2001;98(9):5116–21.PubMedCrossRef

23.

Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 1998;95(25):14863–8.PubMedCrossRef

24.

Too CK, Vickaryous N, Boudreau RT, Sangster SM. Identification and nuclear localization of a novel prolactin and cytokine-responsive carboxypeptidase D. Endocrinology 2001;142(3):1357–67.PubMedCrossRef

25.

Cox GW, Mathieson BJ, Gandino L, Blasi E, Radzioch D, Varesio L. Heterogeneity of hematopoietic cells immortalized by v-myc/v-raf recombinant retrovirus infection of bone marrow or fetal liver. J Natl Cancer Inst 1989;81(19):1492–6.PubMedCrossRef

26.

Hadkar V, Skidgel RA. Carboxypeptidase D is up-regulated in raw 264.7 macrophages and stimulates nitric oxide synthesis by cells in arginine-free medium. Mol Pharmacol 2001;59(5):1324–32.PubMed

27.

Swaisgood CM, Schmitt D, Eaton D, Plow EF. In vivo regulation of plasminogen function by plasma carboxypeptidase B. J Clin Invest 2002;110(9):1275–82.PubMedCrossRef

28.

Matthews KW, Mueller-Ortiz SL, Wetsel RA. Carboxypeptidase N: a pleiotropic regulator of inflammation. Mol Immunol 2004;40(11):785–93.PubMedCrossRef

29.

Leurs J, Hendriks D. Carboxypeptidase U (TAFIa): a metallocarboxypeptidase with a distinct role in haemostasis and a possible risk factor for thrombotic disease. Thromb Haemost 2005;94(3):471–87.PubMed

30.

Krause SW, Rehli M, Andreesen R. Carboxypeptidase M as a marker of macrophage maturation. Immunol Rev 1998;161:119–27.PubMedCrossRef

31.

Hook VY. Regulation of carboxypeptidase H by inhibitory and stimulatory mechanisms during neuropeptide precursor processing. Cell Mol Neurobiol 1988;8(1):49–55.PubMedCrossRef

32.

Swaisgood CM, Schmitt D, Eaton D, Plow EF. In vivo regulation of plasminogen function by plasma carboxypeptidase B. J Clin Invest 2002;110(9):1275–82.PubMedCrossRef

33.

34.

Hook VY. Regulation of carboxypeptidase H by inhibitory and stimulatory mechanisms during neuropeptide precursor processing. Cell Mol Neurobiol 1988;8(1):49–55.PubMedCrossRef

35.

Reverter D, Maskos K, Tan F, Skidgel RA, Bode W. Crystal structure of human carboxypeptidase M, a membrane-bound enzyme that regulates peptide hormone activity. J Mol Biol 2004;338(2):257–69.PubMedCrossRef

36.

Kuroki K, Eng F, Ishikawa T, Turck C, Harada F, Ganem D. gp180, a host cell glycoprotein that binds duck hepatitis B virus particles, is encoded by a member of the carboxypeptidase gene family. J Biol Chem 1995;270(25):15022–8.PubMedCrossRef

37.

Song L, Fricker LD. Purification and characterization of carboxypeptidase D, a novel carboxypeptidase E-like enzyme, from bovine pituitary. J Biol Chem 1995;270(42):25007–13.PubMedCrossRef

38.

McGwire GB, Tan F, Michel B, Rehli M, Skidgel RA. Identification of a membrane-bound carboxypeptidase as the mammalian homolog of duck gp180, a hepatitis B virus-binding protein. Life Sci 1997;60(10):715–24.PubMedCrossRef

39.

Tan F, Rehli M, Krause SW, Skidgel RA. Sequence of human carboxypeptidase D reveals it to be a member of the regulatory carboxypeptidase family with three tandem active site domains. Biochem J 1997;327(Pt 1):81–7.PubMed

40.

Eng FJ, Novikova EG, Kuroki K, Ganem D, Fricker LD. gp180, a protein that binds duck hepatitis B virus particles, has metallocarboxypeptidase D-like enzymatic activity. J Biol Chem 1998;273(14):8382–8.PubMedCrossRef

41.

Ishikawa T, Murakami K, Kido Y, Ohnishi S, Yazaki Y, Harada F et al. Cloning, functional expression, and chromosomal localization of the human and mouse gp180-carboxypeptidase D-like enzyme. Gene 1998;215(2):361–70.PubMedCrossRef

42.

Song L, Fricker LD. Tissue distribution and characterization of soluble and membrane-bound forms of metallocarboxypeptidase D. J Biol Chem 1996;271(46):28884–9.PubMedCrossRef

43.

Gagnon A, Landry A, Proulx J, Layne MD, Sorisky A. Aortic carboxypeptidase-like protein is regulated by transforming growth factor beta in 3T3-L1 preadipocytes. Exp Cell Res 2005;308(2):265–72.PubMedCrossRef

44.

Qiu P, Ritchie RP, Fu Z, Cao D, Cumming J, Miano JM et al. Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo. Circ Res 2005;97(10):983–91.PubMedCrossRef

45.

Skoudy A, Rovira M, Savatier P, Martin F, Leon-Quinto T, Soria B et al. Transforming growth factor (TGF)beta, fibroblast growth factor (FGF) and retinoid signalling pathways promote pancreatic exocrine gene expression in mouse embryonic stem cells. Biochem J 2004;379(Pt 3):749–56.PubMedCrossRef

46.

Riley DA, Tan F, Miletich DJ, Skidgel RA. Chromosomal localization of the genes for human carboxypeptidase D (CPD) and the active 50-kilodalton subunit of human carboxypeptidase N (CPN1). Genomics 1998;50(1):105–8.PubMedCrossRef

47.

Timblin B, Rehli M, Skidgel RA. Structural characterization of the human carboxypeptidase D gene and its promoter. Int Immunopharmacol 2002;2(13–14):1907–17.PubMedCrossRef

48.

Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis Rheum 1973;3(1):1–54.PubMedCrossRef

49.

Lu LY, Cheng HH, Sung PK, Yeh JJ, Shiue YL, Chen A. Single-nucleotide polymorphisms of transforming growth factor-beta1 gene in Taiwanese patients with systemic lupus erythematosus. J Microbiol Immunol Infect 2004;37(3):145–52.PubMed

50.

Davies KA, Peters AM, Beynon HL, Walport MJ. Immune complex processing in patients with systemic lupus erythematosus. In vivo imaging and clearance studies. J Clin Invest 1992;90(5):2075–83.PubMedCrossRef

51.

Yurasov S, Hammersen J, Tiller T, Tsuiji M, Wardemann H. B-cell tolerance checkpoints in healthy humans and patients with systemic lupus erythematosus. Ann N Y Acad Sci 2005;1062:165–74.PubMedCrossRef

52.

Chen YF, Morel L. Genetics of T cell defects in lupus. Cell Mol Immunol 2005;2(6):403–9.

53.

Sanford AN, Suriano AR, Herche D, Dietzmann K, Sullivan KE. Abnormal apoptosis in chronic granulomatous disease and autoantibody production characteristic of lupus. Rheumatology (Oxford) 2006;45(2):178–81.CrossRef

54.

Giese A, Stuhlsatz S, Daubener W, MacKenzie CR. Inhibition of the growth of Toxoplasma gondii in immature human dendritic cells is dependent on the expression of TNF-alpha receptor 2. J Immunol 2004;173(5):3366–74.PubMed

55.

Cairns AP, Crockard AD, Bell AL. The CD14+ CD16+ monocyte subset in rheumatoid arthritis and systemic lupus erythematosus. Rheumatol Int 2002 Mar;21(5):189–92.PubMed

56.

Sanchez-Torres C, Garcia-Romo GS, Cornejo-Cortes MA, Rivas-Carvalho A, Sanchez-Schmitz G. CD16+ and CD16- human blood monocyte subsets differentiate in vitro to dendritic cells with different abilities to stimulate CD4+ T cells. Int Immunol 2001;13(12):1571–81.PubMedCrossRef

Titel: Carboxypeptidase D: A Novel TGF-β Target Gene Dysregulated in Patients with Lupus Erythematosus
verfasst von: Norman-Philipp Hoff
Daniel Degrandi
Ulrich Hengge
Klaus Pfeffer
Jens Ulrich Wurthner
Publikationsdatum: 01.11.2007
Verlag: Springer US
Erschienen in: Journal of Clinical Immunology / Ausgabe 6/2007
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-007-9118-7

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