Autocrine interleukin-6 production in renal cell carcinoma: evidence for the involvement of p53.

Interleukin (IL)-6 is an autocrine growth factor for renal cell carcinoma (RCC). We sought to determine whether p53 regulates constitutive IL-6 production. RCC cell lines containing mutant (mut) p53 produced higher levels of IL-6 than those containing wild-type (wt) p53 (P < 0.05). Transfection of wt p53 into RCC cell lines bearing mut p53 (UOK 121LN) or wt p53 (A498 and ACHN) resulted in repression of IL-6 promoter chloramphenicol acetyltransferase activity (P < 0.05). Mutant p53 was either less effective at repressing IL-6 promoter activity (ACHN cells) or enhanced IL-6 promoter activity (A498 cells). A498 cells stably transfected with mut p53 produced higher levels of IL-6 than A498 cells transfected with an empty expression vector (P < 0.05). Electrophoretic mobility shift assays showed decreased binding of CAAT enhancer binding protein, cyclic AMP responsive element binding protein, +/- nuclear factor-kappaB transcription factors to the IL-6 promoter in various RCC cell lines transfected with wt p53 (P < 0.05) but not in those transfected with mut p53. These data suggest that: (a) mutation of p53 contributes to the overexpression of IL-6 in RCC; and (b) wt p53 represses IL-6 expression, at least in part, by interfering with specific transcription factor binding to the IL-6 promoter.

[1]  S. Akira,et al.  Interleukin-6 in biology and medicine. , 1993, Advances in immunology.

[2]  K. Kinzler,et al.  Oncogenic forms of p53 inhibit p53-regulated gene expression. , 1992, Science.

[3]  J. Blay,et al.  Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. , 1992, Cancer research.

[4]  R. Kurzrock,et al.  Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin's disease and with B symptoms. , 1993, Cancer research.

[5]  B. Seizinger,et al.  Repression of the basal c-fos promoter by wild-type p53. , 1992, Nucleic acids research.

[6]  M. Minden,et al.  Interleukin-6 levels in the plasma of patients with lymphoma. , 1992, Leukemia & lymphoma.

[7]  T. Fujioka,et al.  Infrequent Mutation of p53 Gene in Human Renal Cell Carcinoma Detected by Polymerase Chain Reaction Single‐strand Conformation Polymorphism Analysis , 1992, Japanese journal of cancer research : Gann.

[8]  R. Kreienberg,et al.  p53 mutant His175 identified in a newly established fallopian tube carcinoma cell line secreting interleukin 6 , 1994, FEBS letters.

[9]  T. Hirano,et al.  Distribution of interleukin-6 in normal and diseased human kidney. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[10]  D. Pim,et al.  Monoclonal antibodies specific for simian virus 40 tumor antigens , 1981, Journal of virology.

[11]  H. Karasuyama,et al.  Autocrine growth and tumorigenicity of interleukin 2-dependent helper T cells transfected with IL-2 gene , 1989, The Journal of experimental medicine.

[12]  T. Pritts,et al.  The transcription factor activator protein-1 is activated and interleukin-6 production is increased in interleukin-1beta-stimulated human enterocytes. , 2000, Shock.

[13]  J. Simons,et al.  Interleukin-6: a candidate mediator of human prostate cancer morbidity. , 1995, Urology.

[14]  V. Rotter,et al.  Wild-type but not mutant p53 can repress transcription initiation in vitro by interfering with the binding of basal transcription factors to the TATA motif. , 1993, Oncogene.

[15]  M. Murai,et al.  Autocrine growth promotion by multiple hematopoietic growth factors in the established renal cell carcinoma line KU-19–20 , 2000, Cell and Tissue Research.

[16]  R. Kurzrock,et al.  Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  C. Dinarello,et al.  Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. , 1990, Blood.

[18]  T. Hirano,et al.  Enhanced expression of interleukin-6 in primary human renal cell carcinomas. , 1991, Journal of the National Cancer Institute.

[19]  E. Harlow,et al.  Uniform Nomenclature for Monoclonal Antibodies Directed Against Virus-Coded Proteins of Simian Virus 40 and Polyoma Virus , 1982, Journal of virology.

[20]  F. Kashanchi,et al.  Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. , 1997, Blood.

[21]  S. Akira,et al.  A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Snick,et al.  Interleukin-6: an overview. , 1990, Annual review of immunology.

[23]  P. Sehgal,et al.  Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBP beta (NF-IL6) activity by p53 species. , 1993, The Journal of biological chemistry.

[24]  M. Yaniv,et al.  Wild-type p53 can down-modulate the activity of various promoters. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  C. Cordon-Cardo,et al.  Allelic deletions in renal tumors: histopathological correlations. , 1993, Cancer research.

[26]  L. Crawford,et al.  Overexpression of normal human p53 in established fibroblasts leads to their tumorigenic conversion. , 1989, Oncogene research.

[27]  S. Akira,et al.  Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[28]  L. Crawford,et al.  Characterization of the human p53 gene , 1986, Molecular and cellular biology.

[29]  J. H. Kim,et al.  Cytokine production in primary histoculture by human normal kidney, renal cell carcinoma and benign renal angiomyolipoma tissues. , 1998, Anticancer research.

[30]  J. Berek,et al.  Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer. , 1991, American journal of obstetrics and gynecology.

[31]  A. Deisseroth,et al.  Interaction of nuclear proteins with an AP‐1/CRE‐like promoter sequence in the human TNF‐α gene , 1994 .

[32]  M. Marberger,et al.  mdm2 expression as a prognostic indicator in clear cell renal cell carcinoma: comparison with p53 overexpression and clinicopathological parameters. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  G. Clayman,et al.  Interleukin-1 regulates interleukin-6 secretion in human oral squamous cell carcinoma in vitro: possible influence of p53 but not human papillomavirus E6/E7. , 1998, Cancer research.

[34]  L. Old,et al.  Tumor necrosis factor (TNF). , 1985, Science.

[35]  B. Klein,et al.  Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma. , 1989, Blood.

[36]  T. Shenk,et al.  Relief of p53-mediated transcriptional repression by the adenovirus E1B 19-kDa protein or the cellular Bcl-2 protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Masahiro Yamamoto,et al.  Interleukin‐6 (IL‐6) functions as an in vitro autocrine growth factor in renal cell carcinomas , 1989, FEBS letters.

[38]  M. Nerenberg,et al.  Binding and Functional Effects of Transcriptional Factor Sp1 on the Murine Interleukin-6 Promotor (*) , 1996, The Journal of Biological Chemistry.

[39]  E. D. de Vries,et al.  Differential regulation of IL‐6 promoter activity in a human ovarian‐tumor cell line transfected with various p53 mutants: Involvement of AP‐1 , 1999, International journal of cancer.

[40]  N. Webster,et al.  Repression of the insulin receptor promoter by the tumor suppressor gene product p53: a possible mechanism for receptor overexpression in breast cancer. , 1996, Cancer research.

[41]  T. Libermann,et al.  Activation of interleukin-6 gene expression through the NF-kappa B transcription factor , 1990 .

[42]  O. Yoshida,et al.  Sensitization of human renal cell carcinoma cells to cis-diamminedichloroplatinum(II) by anti-interleukin 6 monoclonal antibody or anti-interleukin 6 receptor monoclonal antibody. , 1995, Cancer research.

[43]  F. Herrmann,et al.  Interferon‐gamma interrupts autocrine growth mediated by endogenous interleukin‐6 in renal‐cell carcinoma , 1991, International journal of cancer.

[44]  U. Santhanam,et al.  Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Levine,et al.  Two domains of p53 interact with the TATA-binding protein, and the adenovirus 13S E1A protein disrupts the association, relieving p53-mediated transcriptional repression , 1995, Molecular and cellular biology.

[46]  D. Longo,et al.  p53 mutation is associated with progression in follicular lymphomas. , 1993, Blood.

[47]  T. Ishikawa,et al.  Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. , 1995, Cancer research.

[48]  T. Soussi,et al.  Linear antigenic sites defined by the B-cell response to human p53 are localized predominantly in the amino and carboxy-termini of the protein. , 1994, Oncogene.

[49]  Wei Zhang,et al.  Novel DNA binding of p53 mutants and their role in transcriptional activation. , 1993, Oncogene.

[50]  E. Tartour,et al.  IL-6 is a survival prognostic factor in renal cell carcinoma. , 1997, Immunology letters.

[51]  G. Köhler,et al.  Pro-Inflammatory and T Cell Inhibitory Cytokines Are Secreted at High Levels in Tumor Cell Cultures of Human Renal Cell Carcinoma , 1999, European Urology.

[52]  T. Hirano,et al.  Molecular biology and immunology of interleukin-6. , 1992, Research in immunology.

[53]  A. Kimchi,et al.  Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6 , 1991, Nature.

[54]  M. Manns,et al.  p53 Represses CAAT Enhancer-binding Protein (C/EBP)-dependent Transcription of the Albumin Gene , 1999, The Journal of Biological Chemistry.

[55]  G. Niehans,et al.  Association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma. , 1994, Journal of the National Cancer Institute.

[56]  D. Green,et al.  Dominant-negative p53 mutations in rheumatoid arthritis. , 1999, Arthritis and rheumatism.

[57]  N. Masumori,et al.  Interleukin-6 in renal cell carcinoma. , 1992, The Journal of urology.

[58]  N. Rioux-Leclercq,et al.  Value of immunohistochemical Ki-67 and p53 determinations as predictive factors of outcome in renal cell carcinoma. , 2000, Urology.

[59]  G. Zambetti,et al.  Wild-type p53 binds to the TATA-binding protein and represses transcription. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[60]  P. Sehgal,et al.  Modulation of Interleukin-6-induced Plasma Protein Secretion in Hepatoma Cells by p53 Species (*) , 1995, The Journal of Biological Chemistry.

[61]  J. Pipas,et al.  Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53 , 1993, Nature.

[62]  S. Akira,et al.  IL‐6 and NF‐IL6 in Acute‐Phase Response and Viral Infection , 1992, Immunological reviews.

[63]  G. Brandner,et al.  Monoclonal antibodies against simian virus 40 nuclear large T tumour antigen: epitope mapping, papova virus cross‐reaction and cell surface staining. , 1984, The EMBO journal.

[64]  E. Appella,et al.  Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell nuclear antigen expression. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[65]  D. Crowe.  Retinoic acid receptor beta induces terminal differentiation of squamous cell carcinoma lines in the absence of cyclin-dependent kinase inhibitor expression. , 1998, Cancer research.

[66]  D. Lane,et al.  Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. , 1990, The EMBO journal.

[67]  木下 茂美.  A member of the C/EBP family, NF-IL6β, forms a heterodimer and transcriptionally synergizes with NF-IL6 , 1993 .

[68]  W. Linehan,et al.  Chromosome 17p deletions and p53 mutations in renal cell carcinoma. , 1993, Cancer research.

[69]  C. Miller,et al.  The p53 activation domain binds the TATA box-binding polypeptide in Holo-TFIID, and a neighboring p53 domain inhibits transcription , 1993, Molecular and cellular biology.

[70]  P. Sehgal,et al.  Transcriptional regulation of the interferon-beta 2/B cell differentiation factor BSF-2/hepatocyte-stimulating factor gene in human fibroblasts by other cytokines. , 1988, Journal of immunology.

[71]  K. Kinzler,et al.  Definition of a consensus binding site for p53 , 1992, Nature Genetics.

[72]  F. Rollwagen,et al.  IL-6 rescues enterocytes from hemorrhage induced apoptosis in vivo and in vitro by a bcl-2 mediated mechanism. , 1998, Clinical immunology and immunopathology.

[73]  É. Lepage,et al.  Tumour necrosis factor-α, interleukin-1β and interleukin-6 in patients with renal cell carcinoma , 1994 .

[74]  P. Sehgal,et al.  Regulation of IL6 gene expression. , 1992, Research in immunology.

[75]  H. Asaoku,et al.  Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas , 1988, Nature.

[76]  O. Halevy,et al.  Different tumor-derived p53 mutants exhibit distinct biological activities. , 1990, Science.