Regulation of CD30 Antigen Expression and Its Potential Significance for Human Disease
2000; Elsevier BV; Volume: 156; Issue: 5 Linguagem: Inglês
10.1016/s0002-9440(10)65018-3
ISSN1525-2191
Autores Tópico(s)Immunotherapy and Immune Responses
ResumoCD30 antigen, a member of the tumor necrosis factor (TNF) receptor superfamily,1Durkop ABC Latza U Hummel M Eitelbach F Seed B Stein H Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin's disease.Cell. 1992; 68: 421-427Abstract Full Text PDF PubMed Scopus (609) Google Scholar, 2Smith CA Gruss HJ Davis T Anderson D Farrah T Baker E Sutherland GR Brannan CI Copeland NG Jenkins NA Grabstein KH Gliniak B McAlister IB Fanslow W Alderson M Falk B Gimpel S Gillis S Din WS Goodwin RG Armitage RJ CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF.Cell. 1993; 73: 1349-1360Abstract Full Text PDF PubMed Scopus (520) Google Scholar, 3Smith CA Farrah T Goodwin RG The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death.Cell. 1994; 76: 959-962Abstract Full Text PDF PubMed Scopus (1845) Google Scholar was originally identified as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells by use of the monoclonal antibody Ki-1.4Schwab U Stein H Gerdes J Lemke H Kirchner J Schaadt M Diehl V Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin's disease and a subset of normal lymphoid cells.Nature. 1982; 299: 65-67Crossref PubMed Scopus (749) Google Scholar, 5Stein H Mason DY Gerdes J O'Connor N Wainscoat J Pallesen G Gatter K Falini B Delsol G Lemke H Schwarting R Lennert K The expression of the Hodgkin's disease-associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells.Blood. 1985; 66: 848-858Crossref PubMed Google Scholar CD30 antigen normally is expressed by a subset (15–20%) of CD45RO+ T cells after activation by a variety of stimuli.6Ellis TN Simms PE Slivnick DJ Jack H Fisher RI CD30 is a signal-transducing molecule that defines a subset of human CD45RO+ T-cells.J Immunol. 1993; 151: 2380-2389PubMed Google Scholar Its expression is stimulated by interleukin (IL)-4 during lineage commitment of human naïve T cells7Nakamura T Lee RK Nam SY Al-Ramadi BK Koni PA Bottomly K Podack ER Flavell RA Reciprocal regulation of CD30 expression on CD4+ T cells by IL-4 and IFN-γ.J Immunol. 1997; 158: 2090-2098PubMed Google Scholar, 8Annunziato F Manetti R Cosmi L Galli G Heusser CH Romagnani S Maggi E Opposite role for interleukin-4 and inteferon-gamma on CD30 and lymphocyte activation gene-3 (LAG-3) expression by activated naïve T cells.Eur J Immunol. 1997; 27: 2239-2244Crossref PubMed Scopus (56) Google Scholar and is augmented by the presence of CD28 costimulatory signals.9Gilfillan MC Noel PJ Podack ER Reiner SL Thompson CB Expression of the costimulatory receptor CD30 is regulated by both CD28 and cytokines.J Immunol. 1998; 160: 2180-2187PubMed Google Scholar CD30 also is expressed at variable levels in different non-Hodgkin's lymphomas (NHL) as well as in several virally transformed T and B cell lines.5Stein H Mason DY Gerdes J O'Connor N Wainscoat J Pallesen G Gatter K Falini B Delsol G Lemke H Schwarting R Lennert K The expression of the Hodgkin's disease-associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells.Blood. 1985; 66: 848-858Crossref PubMed Google Scholar, 10Gruss HJ Dower SK Tumor necrosis ligand superfamily: involvement in the pathology of malignant lymphomas.Blood. 1995; 85: 3378-3404Crossref PubMed Google Scholar In particular, CD30 is a specific marker of a subset of peripheral T cell NHLs known as anaplastic large cell lymphomas (ALCL).5Stein H Mason DY Gerdes J O'Connor N Wainscoat J Pallesen G Gatter K Falini B Delsol G Lemke H Schwarting R Lennert K The expression of the Hodgkin's disease-associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells.Blood. 1985; 66: 848-858Crossref PubMed Google Scholar More recently, CD30 preferential expression has been detected on a subset of tissue and circulating CD4+ and CD8+ T cells producing mainly Th2 cytokines in immunoreactive conditions.11Del Prete G De Carli M Almerigogna F Daniel CK D' Elios MM Zanguoghi G Vinante F Pizzolo G Romagnani S Preferential expression of CD30 by human CD4+ T cells producing Th2-type cytokines.FASEB J. 1995; : 81-86PubMed Google Scholar, 12Manetti R Annunziato F Biagiotti R Giudizi MG Piccini MP Giannarini L Sampognaro S Parronichi P Vinante F Pizzolo G Maggi E Romagnani S CD30 expression by CD8+ T cells producing type 2 helper cytokines: Evidence for large numbers of CD8+ CD30+ T cell clones in human immunodeficiency virus infection.J Exp Med. 1994; 180: 2407-2411Crossref PubMed Google Scholar, 13Bengtsson A Hohansson C Linder MT Hallden G van der Ploeg I Scheynius A Not only Th2 cells but also Th1 and Th0 cells express CD30 after activation.J Leukoc Biol. 1995; 58: 683-689PubMed Google Scholar, 14Hamann D Hilkens CM Grogan JL Lens SM Kapsenberg ML Yazdanbakhsh M van Lier RA CD30 expression does not discriminate between human Th1- and Th2-type T cells.J Immunol. 1996; 156: 1387-1391PubMed Google Scholar The biological significance of the CD30 molecule is related to the existence of a natural ligand, CD30L, a member of the TNF ligand superfamily recently identified in murine T cells and in human CD3-activated peripheral blood T cells, monocytes induced with lipopolysaccharide, and in eosinophils, at highest levels in pathological conditions such as Hodgkin's lymphoma (HL) and the hypereosinophilic syndrome.2Smith CA Gruss HJ Davis T Anderson D Farrah T Baker E Sutherland GR Brannan CI Copeland NG Jenkins NA Grabstein KH Gliniak B McAlister IB Fanslow W Alderson M Falk B Gimpel S Gillis S Din WS Goodwin RG Armitage RJ CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF.Cell. 1993; 73: 1349-1360Abstract Full Text PDF PubMed Scopus (520) Google Scholar, 15Pinto A Aldinucci D Gloghini A Zagonel V Degan M Improta S Juzbasic S Todesco M Perin V Gattei V Herrmann F Gruss H-J Carbone A Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line.Blood. 1996; 88: 3299-3305PubMed Google Scholar Cross-linking of CD30 results in signal transduction with increased levels of intracellular Ca2+.6Ellis TN Simms PE Slivnick DJ Jack H Fisher RI CD30 is a signal-transducing molecule that defines a subset of human CD45RO+ T-cells.J Immunol. 1993; 151: 2380-2389PubMed Google Scholar Engagement of CD30 by CD30L appears to up-regulate apoptosis of mature T lymphocytes in peripheral lymphoid organs of mice, rendering these lymphocytes susceptible to cell death after withdrawal of T cell receptor signaling.16Telford WG Nam SY Podack ER Miller RA CD30-regulated apoptosis in murine CD8 T cells after cessation of TCR signals.Cell Immunol. 1997; 182: 125-136Crossref PubMed Scopus (44) Google Scholar CD30 appears to have an important immunoregulatory role in normal T cell development. Within the thymus, CD30L is highly expressed on medullary thymic epithelial cells and on Hassal's corpuscles.17Romagnani P Annuziatoa F Manetti R Mavilia C Lasagni L Manuelli C Vanelli V Maggi E Pupilli C Romagnani S High CD30 ligand expression by epithelial cells and Hassal's corpuscles in the medulla of the thymus.Blood. 1998; 91: 3323-3333PubMed Google Scholar In mice, CD30 overexpression helps to eliminate autoreactive T cells through negative selection of CD4+/CD8+ thymocytes by a caspase-dependent mechanism, a process that it totally prevented by bcl-2.18Chiarle R Podda A Prolla G Podack ER Thorbecke GH Inghirami G CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a bcl-2 sensitive pathway.J Immunol. 1999; 163: 194-205PubMed Google Scholar As expected, CD30−/− mice have elevated numbers of thymocytes and activation-induced death of thymocytes after CD3 cross-linking is impaired both in vitro and in vivo.19Amakawa R Hakem A Kundig TM Matsuyama T Simard JJ Timms E Wakeham A Mittruecker HW Griesser H Takimoto H Schmits R Shahinian A Ohashi P Penninger JM Mak TW Impaired negative selection of T cells in Hodgkin's disease antigen CD30-deficient mice.Cell. 1996; 84: 551-562Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar The functional relevance of CD30/CD30L interaction in human lymphomas is beginning to be understood. Recombinant CD30L expressed on the surface of cultured cells was tested for biological activities on a variety of CD30+ human lymphoma cell lines.20Gruss HJ Boiani N Williams DE Armitage RH Smith CA Goodwin RG Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines.Blood. 1994; 83: 2045-2056Crossref PubMed Google Scholar It was demonstrated that CD30L+ cells enhance proliferation of HL cell lines with a T cell genotype/phenotype. in contrast they have no effect on HL cell lines with a B cell genotype/phenotype, and an antiproliferative effect on certain CD30+ T cell ALCL lines, including a cytolytic effect and a cytostatic component inducing cell cycle arrest.15Pinto A Aldinucci D Gloghini A Zagonel V Degan M Improta S Juzbasic S Todesco M Perin V Gattei V Herrmann F Gruss H-J Carbone A Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line.Blood. 1996; 88: 3299-3305PubMed Google Scholar, 20Gruss HJ Boiani N Williams DE Armitage RH Smith CA Goodwin RG Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines.Blood. 1994; 83: 2045-2056Crossref PubMed Google Scholar Therefore, CD30L is capable of transducing signals leading to either cell death or proliferation through its specific cognate molecule, CD30. Taken together, these data demonstrate pleiotropic biological activities of CD30L on different CD30+ lymphoma cell lines and indicate that CD30/CD30L interaction probably plays an important role in the pathophysiology of HL and ALCL. The molecular mechanism(s) underlying deregulated expression of CD30 in these lymphomas is unknown but appears to be independent of infection with Epstein-Barr virus (EBV) or human T-cell leukemia virus-1 (HTLV-1) since CD30 is strongly expressed on lymphoma cell lines which lack these viruses,21Drexler H Recent results on the biology of Hodgkin and Reed-Sternberg cells. II. Continuous cell lines.Leukemia Lymphoma. 1993; 9: 1-26Crossref PubMed Scopus (136) Google Scholar and EBV is absent in approximately 40 to 50. of primary HL of immunocompetent patients in Western countries.22Weiss LM Chen YY Lui XF Shibata D Epstein-Barr virus and Hodgkin's disease: a correlative in situ hybridization and polymerase chain reaction study.Am J Pathol. 1991; 139: 1259-1265PubMed Google Scholar In this issue of The American Journal of Pathology, Croager and coworkers describe insightful experiments which begin to clarify one aspect of the regulation of CD30 expression.23Croager E Gout AM Abraham LJ Involvement of Sp1 and microsatellite repressor sequences in the transcriptional control of the human CD30 gene.Am J Pathol. 2000; 156: 1723-1731Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar They define three key regulatory regions important in the transcriptional control of CD30. In common with other members of the TNF receptor/TNF ligand superfamily, CD30 lacks a canonical TATA box commonly used by other genes as an anchor for basal transcriptional machinery. Croager et al found that transcription factor Sp1 acts as a surrogate for the TATA motif, recruiting TATA binding proteins which are normally required for initiation of transcription. A downstream promoter element was found to direct both the accuracy and level of CD30 transcription. Finally, an upstream microsatellite region that binds proteins which suppress transcriptional activity of the CD30 promoter was recognized. The essential feature of this microsatellite is a (CCAT)n sequence which alone was capable of repressing transcription from the CD30 promoter. Croager et al have established that shortened versions of this microsatellite repressor have lower levels of repression in vitro, a finding that may have relevance in lymphomas and other diseases that exhibit increased CD30 expression. The microsatellite was found to contain differences of as many as ten CCAT repeats in a preliminary study of DNA samples from seven random donors. A similar degree of microsatellite polymorphism was uncovered in a limited survey of human tumor cell lines, but none of these were derived from HL or CD30+ ALCL. With such a high degree of polymorphism in a small size sample, it may be anticipated that a more comprehensive study of patients with CD30+ lymphomas and autoimmune diseases (see below) may reveal recurrent polymorphisms that predispose them to overexpression of CD30 with corresponding disease phenotypes. Supporting the hypothesis that polymorphisms resulting in variable microsatellite lengths can be associated with a predisposition for disease is the fragile X syndrome.24Fu Y-H Kuhl DPA Pizzuti A Pieretti M Sutcliffe JS Richards S Verkerk HJMH Holden JJA Fenwick RG Warren ST Oostra BA Nelson DL Caskey CT Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox.Cell. 1991; 67: 1047-1058Abstract Full Text PDF PubMed Scopus (1785) Google Scholar The fragile X syndrome results from variations in a (CGG)n. repeat found in the coding sequence of the FMR-1 gene. Analysis of length variation in the region in normal individuals shows a range of allele sizes varying from a low of 6 to a high of 54 repeats. All alleles with more than 52 repeats are meiotically unstable with a mutation frequency of one, whereas meioses of alleles of 46 repeats and below have shown no mutation. The risk of expansion during oogenesis to the full mutation associated with mental retardation increases with the number of (CGG)n repeats. Microsatellite regions are also prone to insertion/deletion mutations, observed at highest frequency in individuals with defects in DNA mismatch repair enzymes hMHS2 and hMLH1.25Eshelman JR Markowitz SD Microsatellite instability in inherited and sporadic neoplasms.Curr Opin Oncol. 1995; 7: 83-85Crossref PubMed Scopus (248) Google Scholar Such individuals are at increased risk of developing colorectal cancers with inactivating mutations arising in microsatellites of the pro-apoptotic BAX gene26Rampino N Yamamoto H Ionov Y Li Y Sawai H Reed JC Perucho M Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype.Science. 1997; 275: 967-969Crossref PubMed Scopus (1238) Google Scholar and the type II receptor for transforming growth factor-β, which normally has a growth inhibitory function.27Markowitz S Wang J Myeroff L Parsons R Sun LZ Lutterbaugh J Fan RS Zborowska E Kinzler KW Vogelstein B Brattain M Wilson JKV Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability.Science. 1995; 268: 1336-1338Crossref PubMed Scopus (2154) Google Scholar The pleiotropic effects of CD30 signaling have been attributed to the nature of the target cell, its state of differention, transformation status and environmental cofactors.20Gruss HJ Boiani N Williams DE Armitage RH Smith CA Goodwin RG Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines.Blood. 1994; 83: 2045-2056Crossref PubMed Google Scholar These pleiotropic effects may also be explained by the divergent pathways of CD30 signal transduction through a family of adapter molecules called TNFR-associated factors (TRAFs) which has at least 6 family members.28Baker SJ Reddy EP Transducers of life and death: TNF receptor superfamily and associated proteins.Oncogene. 1996; 12: 1-9PubMed Google Scholar Signals emanating from the TNFR family diverge downstream of TRAF-2, leading to activation of two important transcription factors, NF-κB and c-Jun N-terminal kinase.29Gedrich RW Gilfillan MC Duckett CS van Dongen JL Thompson CB CD30 contains two binding sites with different specificities for members of the tumor necrosis factor-associated factor family of signal transducing proteins.J Biol Chem. 1996; 271: 12852-12858Crossref PubMed Scopus (155) Google Scholar, 30Aizawa SH Nakano T Ishida R Horie M Nagai M Ito K Yagata H Okomura K Inove J Watanabe T Tumor necrosis factor receptor associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NF-kB activation.J Biol Chem. 1997; 272: 2042-2045Crossref PubMed Scopus (187) Google Scholar, 31Duckett CS Gedrich RW Gilfillan MC Thompson CB Induction of nuclear factor kappa B by the CD30 receptor is mediated by TRAF1 and TRAF2.Mol Cell Biol. 1997; 17: 1535-1542Crossref PubMed Google Scholar, 32Ansieau S Scheffrahn I Mosialos G Brand H Duyster J Kaye K Harada J Dougall B Hübinger G Kiéff E Hermann F Leutz A Gruss H-J Tumor necrosis factor-associated (TRAF)-1, TRAF-2, and TRAF-3 interact in vivo with the CD30 cytoplasmic domain: TRAF-2 mediates CD30-induced nuclear factor kappa B activation.Proc Natl Acad Sci USA. 1996; 93: 14053-14058Crossref PubMed Scopus (72) Google Scholar, 33Hsu H Shu JB Pan MG Goeddel DV TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.Cell. 1996; 84: 299-308Abstract Full Text Full Text PDF PubMed Scopus (1745) Google Scholar, 34Duckett CS Thompson CB CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signalling and the control of cell survival.Genes Dev. 1997; : 2810-2821Crossref PubMed Scopus (192) Google Scholar, 35Boucher LM Marengere LE Lu Y Thukral S Mak TW Binding sites of cytoplasmic effectors TRAF1, 2 and 3 on CD30 and other members of the TNF superfamily.Biochem Biophys Res Commun. 1997; 233: 592-600Crossref PubMed Scopus (89) Google Scholar, 36Tsitsikov EN Wright DA Geha RS CD30 induction of human immunodeficiency virus gene transcription is mediated by TRAF2.Proc Natl Acad Sci USA. 1997; 94: 1390-1395Crossref PubMed Scopus (29) Google Scholar, 37Song HY Regnier CH Kirschning CJ Goeddel DV Rothe M Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kB and c-jun N-terminal kinase is mediated by TRAF2.Proc Natl Acad Sci USA. 1997; 94: 9792-9796Crossref PubMed Scopus (508) Google Scholar NF-κB signaling is activated through recruitment and activation of a series of protein kinases which leads to the translocation of NF-κB into the nucleus. The NF-κB-inducing kinase (NIK) is a mitogen-activated protein (MAP) kinase kinase kinase (MAP3K).38Malinin NL Boldin MP Kovalenko AV Wallach D MAP3K-related kinase involved in induction by TNF-α, CD95 and IL-1.Nature. 1997; 385: 540-544Crossref PubMed Scopus (1171) Google Scholar A substrate of NIK is the IκB complex (IKK), which consists of two subunits, IKKα and IKKβ.39Regnier CH Song HY Gao X Goeddel DV Cao Z Rothe M Indentifcation and characterization of an IkB kinase.Cell. 1997; 90: 373-383Abstract Full Text Full Text PDF PubMed Scopus (1073) Google Scholar, 40Woronicz JD Gao X Cao Z Rothe M Goeddel DV IkB kinase-beta: NF-kB activation and complex formation with IkB kinase-alpha and NIK (see comments).Nature. 1997; 388: 548-554Crossref PubMed Scopus (1926) Google Scholar The IKK complex is essential for the phosphorylation and inactivation of the NF-κB inhibitor protein by IκB.39Regnier CH Song HY Gao X Goeddel DV Cao Z Rothe M Indentifcation and characterization of an IkB kinase.Cell. 1997; 90: 373-383Abstract Full Text Full Text PDF PubMed Scopus (1073) Google Scholar, 40Woronicz JD Gao X Cao Z Rothe M Goeddel DV IkB kinase-beta: NF-kB activation and complex formation with IkB kinase-alpha and NIK (see comments).Nature. 1997; 388: 548-554Crossref PubMed Scopus (1926) Google Scholar, 41Zandi E Rothwarf DM Delhase M Hayakawa M Karin M The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation.Cell. 1997; 91: 243-252Abstract Full Text Full Text PDF PubMed Scopus (1605) Google Scholar IκB is found in the cytosol associated with NF-κB, keeping NF-κB in an inactivated state. Upon phosphorylation and degradation of IκB, NF-κB translocates into the nucleus in an activated state.41Zandi E Rothwarf DM Delhase M Hayakawa M Karin M The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation.Cell. 1997; 91: 243-252Abstract Full Text Full Text PDF PubMed Scopus (1605) Google Scholar, 42Mercurio F Zhu H Murray BW Shevchenko A Bennett BL Li JW Young DB Barbosa M Mann M Manning A Rao A IKK1 and IKK2: Cytokine-activated IkB kinases essential for NF-kB activation.Science. 1997; 278: 860-866Crossref PubMed Scopus (1860) Google Scholar It can then stimulate transcription of a number of cellular genes, eg, IL-6,43Gruss HJ Ulrich D Dower SK Herrman F Brach MA Activation of Hodgkin cells via the CD30 receptor induces autocrine secretion of interleukin-6 engaging the NF-kappa beta transcription factor.Blood. 1996; 87: 2443-2449PubMed Google Scholar that may account for the variable histopathology and clinical symptoms of patients with HL.44Kadin ME Liebowitz DN Cytokines and cytokine receptors in Hodgkin's disease.in: Mauch PM Armitage JO Diehl V Hoppe RT Weiss LM Hodgkin's Disease. Lippincott Williams and Wilkins, Philadelphia1999: 139-157Google Scholar TRAF-2 also activates MEKK-1, another MAP3K, which selectively activates IKK-β, resulting in NF-κB activation. MEKK-1 activation by TRAF-2 also results in activation of stress-activated kinase/c-Jun N-terminal kinase through activation of MEK-4, leading to various biological effects.37Song HY Regnier CH Kirschning CJ Goeddel DV Rothe M Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kB and c-jun N-terminal kinase is mediated by TRAF2.Proc Natl Acad Sci USA. 1997; 94: 9792-9796Crossref PubMed Scopus (508) Google Scholar, 45Lee FS Hagler J Chen ZJ Maniatis T Activation of the IkB kinase complex by MEKK1, a kinase of the JNK pathway.Cell. 1997; 88: 213-222Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar Constitutive activation of NF-κB-RelA prevents Hodgkin/Reed-Sternberg (H/RS) cells in HL from undergoing stress-induced apoptosis; HL cell lines depleted of constitutive NF-κB are no longer able to produce tumors in immunodeficient mice.46Bargou RC Emmerich F Krappmann D Bommert K Mapara MY Arnold W Roger HD Grinstein E Greiner A Scheidereit C Dorken B Constitutive nuclear factor-kappa B-RelA activation is required for proliferation and survival of Hodgkin's tumor cells.J Clin Invest. 1997; 100: 2961-2969Crossref PubMed Scopus (705) Google Scholar It is possible that in HL tissues, NF-κB is up-regulated by CD30/CD30L interactions. The source of CD30L in HL tissues appears to be from activated T cells and eosinophils.15Pinto A Aldinucci D Gloghini A Zagonel V Degan M Improta S Juzbasic S Todesco M Perin V Gattei V Herrmann F Gruss H-J Carbone A Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line.Blood. 1996; 88: 3299-3305PubMed Google Scholar, 47Gruss H-J Pinto A Gloghini A Wright B Boiani N Aldinucci D Gattei V Zagonel V Smith CA Kadin ME von Schilling C Goodwin RG Herrmann F Carbone A CD30 ligand expression in non-malignant and Hodgkin's disease-involved lymphoid tissues.Am J Pathol. 1996; 149: 469-481PubMed Google Scholar The density of eosinophils correlates with a poorer prognosis in nodular sclerosing HL, possibly as their expression of CD30L serves to promote the survival of H/RS cells.48Von Wasielewski R Seth S Franklin J Fischer R Hubner K Hansman ML Diehl V Georgii A Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin's disease, allowing for known prognostic factors.Blood. 2000; 95: 1207-1213PubMed Google Scholar A direct stimulating effect of CD30L expressed by eosinophils on proliferation of HL cell line HDLM-2 was reported by Pinto and coworkers.15Pinto A Aldinucci D Gloghini A Zagonel V Degan M Improta S Juzbasic S Todesco M Perin V Gattei V Herrmann F Gruss H-J Carbone A Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line.Blood. 1996; 88: 3299-3305PubMed Google Scholar However, HDLM-2 has a T cell phenotype and genotype,49Drexler HG Gaedicke G Lok MS Diehl V Minowada J Hodgkin's disease derived cell lines HDLM-2 and L-428: Comparison of morphology, immunological and isoenzyme profiles.Leuk Res. 1986; 10: 487-500Abstract Full Text PDF PubMed Scopus (91) Google Scholar and therefore represents only a small fraction of HL cases.50Muschen M Rajewsky K Brauninger A Baur AS Oudejans JJ Roers A Hansmann M-L Kuppers R Rare occurrence of classical Hodgkin's disease as a T cell lymphoma.J Exp Med. 2000; 191: 387-394Crossref PubMed Scopus (176) Google Scholar, 51Seitz V, Hummel M, Marafioti T, Anagnostopoulos I, Assaf C, Stein H: Detection of clonal T-cell receptor gamma-chain gene-rearrangements in Reed-Sternberg cells of classic Hodgkin's disease. Blood 2000 (in press)Google Scholar In contrast, Gruss and coworkers, who showed similar CD30L enhanced proliferation results for HDLM-2 and L-540, another HL line with T cell characteristics, found that HL cell lines of B cell phenotype and genotype were not further stimulated to proliferate by recombinant CD30L.20Gruss HJ Boiani N Williams DE Armitage RH Smith CA Goodwin RG Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines.Blood. 1994; 83: 2045-2056Crossref PubMed Google Scholar A possible explanation for these results is that the HL lines of B cell type have a high constitutive activation of NF-κB and cannot be further stimulated by engagement with CD30L.46Bargou RC Emmerich F Krappmann D Bommert K Mapara MY Arnold W Roger HD Grinstein E Greiner A Scheidereit C Dorken B Constitutive nuclear factor-kappa B-RelA activation is required for proliferation and survival of Hodgkin's tumor cells.J Clin Invest. 1997; 100: 2961-2969Crossref PubMed Scopus (705) Google Scholar The Sp1 transcription factor, required for initiating transcription of the CD30 gene, is up-regulated by viral activation. Accordingly, Croager and colleagues suggest that in HL, EBV may up-regulate Sp1 leading to H/RS cell overexpression of CD30, and possibly CD40, another TATA-less member of the TNF family.23Croager E Gout AM Abraham LJ Involvement of Sp1 and microsatellite repressor sequences in the transcriptional control of the human CD30 gene.Am J Pathol. 2000; 156: 1723-1731Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar CD40 protects germinal center B cells from apoptosis,52Banchereau J De Paoli P Valle A Garcia E Rousset F Long-term human B cell lines dependent on interleukin-4 and antibody to CD40.Science. 1991; 251: 70-72Crossref PubMed Scopus (532) Google Scholar, 53Liu YJ Mason DY Johnson GD Abbott S Gregory CD Hardie DL Gordon J MacLennen IC Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis.Eur J Immunol. 1991; 21: 1905-1910Crossref PubMed Scopus (395) Google Scholar and therefore could also promote survival of H/RS cells.54Kanzler H Kuppers R Hansmann ML Rajewsky K Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from crippled germinal center B cells.J Exp Med. 1996; 184: 1495-1505Crossref PubMed Scopus (625) Google Scholar Because EBV-latent membrane protein-1 (LMP-1) and CD30 use the same signal transduction pathway of TRAFs to transmit growth signals from the cell membrane to the nucleus,55Mosialos G Birkenbach M Yalamanchili R Van Arsdale T Ware C Kieff E The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family.Cell. 1995; 80: 389-399Abstract Full Text PDF PubMed Scopus (908) Google Scholar, 56Kaye KM Devergne O Harada JN Izumi KM Yalamanchili R Kieff E Mosialos G Tumor necrosis factor receptor associated factor 2 is a mediator of NF-kappa B activation by latent infection membrane protein- 1, the Epstein-Barr virus transforming protein.Proc Natl Acad Sci USA. 1996; 93: 11085-11090Crossref PubMed Scopus (222) Google Scholar, 57Sandberg M Hammerschmidt W Sugden B Characterization of LMP-1's association with TRAF1, TRAF2 and TRAF3.J Virol. 1997; 71: 4649-4656Crossref PubMed Google Scholar, 58Liebowitz D Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients.N Engl J Med. 1998; 338: 1413-1421Crossref PubMed Scopus (190) Google Scholar both direct and indirect effects of EBV on H/RS cell survival are plausible. In two of three cases of EBV-negative HL, clonal deleterious mutations of IkB, which normally maintains NF-κB in an inactive state in the cytosol, were found in H/RS cells, suggesting an alternative pathway for activation of NF-κB in EBV-negative cases.59Jungnickel B Staratschek-Jox A Brauninger A Speiker ABC Wolf J Diehl V Hansmann M-L Rajewsky K Kuppers R Clonal deleterious mutations in the IkBα gene in the malignant cells in Hodgkin's lymphoma.J Exp Med. 2000; 191: 395-401Crossref PubMed Scopus (239) Google Scholar CD30 lacks the death domain of the TNF receptor and Fas antigen, which is required for transduction of an apoptotic signal.2Smith CA Gruss HJ Davis T Anderson D Farrah T Baker E Sutherland GR Brannan CI Copeland NG Jenkins NA Grabstein KH Gliniak B McAlister IB Fanslow W Alderson M Falk B Gim
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