Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Aug;86(2):592–599. doi: 10.1172/JCI114749

Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice.

S J Brandt 1, D M Bodine 1, C E Dunbar 1, A W Nienhuis 1
PMCID: PMC296765  PMID: 2384605

Abstract

Interleukin 6 (IL-6) is an important regulator of the acute phase response, T cell function, and terminal B cell differentiation. Excessive or inappropriate production of this cytokine may be involved in a variety of autoimmune and neoplastic disorders. To investigate the consequences of dysregulated synthesis of IL-6 in vivo, a high-titer recombinant retroviral vector produced in psi-2 packaging cells was used to introduce the coding sequences of murine IL-6 into mouse hematopoietic cells. Congenitally anemic W/Wv mice reconstituted with bone marrow cells transduced with the retroviral vector developed a syndrome characterized by anemia, transient granulocytosis, hypoalbuminemia, and polyclonal hypergammaglobulinemia, with marked splenomegaly and peripheral lymphadenopathy. Extensive plasma cell infiltration of lymph nodes, spleen, liver, and lung was noted. The similarity of these findings to those of multicentric Castleman's disease, taken together with the observation that lymph nodes from these patients elaborate large amounts of this cytokine, suggest that the inappropriate synthesis of IL-6 has a primary role in the pathogenesis of this systemic lymphoproliferative disorder.

Full text

PDF
592

Images in this article

594Image
on p.594
594Image
on p.594
595Image
on p.595
595Image
on p.595
595Image
on p.595
595Image
on p.595
597Image
on p.597
597Image
on p.597
597Image
on p.597
597Image
on p.597

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Armentano D., Yu S. F., Kantoff P. W., von Ruden T., Anderson W. F., Gilboa E. Effect of internal viral sequences on the utility of retroviral vectors. J Virol. 1987 May;61(5):1647–1650. doi: 10.1128/jvi.61.5.1647-1650.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bassin R. H., Tuttle N., Fischinger P. J. Rapid cell culture assay technic for murine leukaemia viruses. Nature. 1971 Feb 19;229(5286):564–566. doi: 10.1038/229564b0. [DOI] [PubMed] [Google Scholar]
  3. CASTLEMAN B., IVERSON L., MENENDEZ V. P. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer. 1956 Jul-Aug;9(4):822–830. doi: 10.1002/1097-0142(195607/08)9:4<822::aid-cncr2820090430>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  4. Castell J. V., Gómez-Lechón M. J., David M., Hirano T., Kishimoto T., Heinrich P. C. Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett. 1988 May 23;232(2):347–350. doi: 10.1016/0014-5793(88)80766-x. [DOI] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Chiu C. P., Moulds C., Coffman R. L., Rennick D., Lee F. Multiple biological activities are expressed by a mouse interleukin 6 cDNA clone isolated from bone marrow stromal cells. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7099–7103. doi: 10.1073/pnas.85.19.7099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  8. Frizzera G., Banks P. M., Massarelli G., Rosai J. A systemic lymphoproliferative disorder with morphologic features of Castleman's disease. Pathological findings in 15 patients. Am J Surg Pathol. 1983 Apr;7(3):211–231. doi: 10.1097/00000478-198304000-00001. [DOI] [PubMed] [Google Scholar]
  9. Frizzera G. Castleman's disease and related disorders. Semin Diagn Pathol. 1988 Nov;5(4):346–364. [PubMed] [Google Scholar]
  10. Frizzera G., Peterson B. A., Bayrd E. D., Goldman A. A systemic lymphoproliferative disorder with morphologic features of Castleman's disease: clinical findings and clinicopathologic correlations in 15 patients. J Clin Oncol. 1985 Sep;3(9):1202–1216. doi: 10.1200/JCO.1985.3.9.1202. [DOI] [PubMed] [Google Scholar]
  11. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  12. Grossman R. M., Krueger J., Yourish D., Granelli-Piperno A., Murphy D. P., May L. T., Kupper T. S., Sehgal P. B., Gottlieb A. B. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6367–6371. doi: 10.1073/pnas.86.16.6367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guerne P. A., Zuraw B. L., Vaughan J. H., Carson D. A., Lotz M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest. 1989 Feb;83(2):585–592. doi: 10.1172/JCI113921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hack C. E., De Groot E. R., Felt-Bersma R. J., Nuijens J. H., Strack Van Schijndel R. J., Eerenberg-Belmer A. J., Thijs L. G., Aarden L. A. Increased plasma levels of interleukin-6 in sepsis. Blood. 1989 Oct;74(5):1704–1710. [PubMed] [Google Scholar]
  15. Hanson C. A., Frizzera G., Patton D. F., Peterson B. A., McClain K. L., Gajl-Peczalska K. J., Kersey J. H. Clonal rearrangement for immunoglobulin and T-cell receptor genes in systemic Castleman's disease. Association with Epstein-Barr virus. Am J Pathol. 1988 Apr;131(1):84–91. [PMC free article] [PubMed] [Google Scholar]
  16. Hirano T., Matsuda T., Turner M., Miyasaka N., Buchan G., Tang B., Sato K., Shimizu M., Maini R., Feldmann M. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988 Nov;18(11):1797–1801. doi: 10.1002/eji.1830181122. [DOI] [PubMed] [Google Scholar]
  17. Hirano T., Taga T., Yasukawa K., Nakajima K., Nakano N., Takatsuki F., Shimizu M., Murashima A., Tsunasawa S., Sakiyama F. Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc Natl Acad Sci U S A. 1987 Jan;84(1):228–231. doi: 10.1073/pnas.84.1.228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hoang T., Haman A., Goncalves O., Wong G. G., Clark S. C. Interleukin-6 enhances growth factor-dependent proliferation of the blast cells of acute myeloblastic leukemia. Blood. 1988 Aug;72(2):823–826. [PubMed] [Google Scholar]
  19. Horii Y., Muraguchi A., Iwano M., Matsuda T., Hirayama T., Yamada H., Fujii Y., Dohi K., Ishikawa H., Ohmoto Y. Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol. 1989 Dec 15;143(12):3949–3955. [PubMed] [Google Scholar]
  20. Houssiau F. A., Devogelaer J. P., Van Damme J., de Deuxchaisnes C. N., Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988 Jun;31(6):784–788. doi: 10.1002/art.1780310614. [DOI] [PubMed] [Google Scholar]
  21. Ikebuchi K., Wong G. G., Clark S. C., Ihle J. N., Hirai Y., Ogawa M. Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9035–9039. doi: 10.1073/pnas.84.24.9035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ishibashi T., Kimura H., Shikama Y., Uchida T., Kariyone S., Hirano T., Kishimoto T., Takatsuki F., Akiyama Y. Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood. 1989 Sep;74(4):1241–1244. [PubMed] [Google Scholar]
  23. Ishibashi T., Kimura H., Uchida T., Kariyone S., Friese P., Burstein S. A. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5953–5957. doi: 10.1073/pnas.86.15.5953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kikutani H., Taga T., Akira S., Kishi H., Miki Y., Saiki O., Yamamura Y., Kishimoto T. Effect of B cell differentiation factor (BCDF) on biosynthesis and secretion of immunoglobulin molecules in human B cell lines. J Immunol. 1985 Feb;134(2):990–995. [PubMed] [Google Scholar]
  25. Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed] [Google Scholar]
  26. Klein B., Zhang X. G., Jourdan M., Content J., Houssiau F., Aarden L., Piechaczyk M., Bataille R. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood. 1989 Feb;73(2):517–526. [PubMed] [Google Scholar]
  27. Kohase M., Henriksen-DeStefano D., May L. T., Vilcek J., Sehgal P. B. Induction of beta 2-interferon by tumor necrosis factor: a homeostatic mechanism in the control of cell proliferation. Cell. 1986 Jun 6;45(5):659–666. doi: 10.1016/0092-8674(86)90780-4. [DOI] [PubMed] [Google Scholar]
  28. Koike K., Nakahata T., Takagi M., Kobayashi T., Ishiguro A., Tsuji K., Naganuma K., Okano A., Akiyama Y., Akabane T. Synergism of BSF-2/interleukin 6 and interleukin 3 on development of multipotential hemopoietic progenitors in serum-free culture. J Exp Med. 1988 Sep 1;168(3):879–890. doi: 10.1084/jem.168.3.879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. LEE S. L., ROSNER F., RIVERO I., FELDMAN F., HURWITZ A. REFRACTORY ANEMIA WITH ABNORMAL IRON METABOLISM: ITS REMISSION AFTER RESECTION OF HYPERPLASTIC MEDIASTINAL LYMPH NODES. N Engl J Med. 1965 Apr 15;272:761–766. doi: 10.1056/NEJM196504152721502. [DOI] [PubMed] [Google Scholar]
  30. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  31. Marinkovic S., Jahreis G. P., Wong G. G., Baumann H. IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo. J Immunol. 1989 Feb 1;142(3):808–812. [PubMed] [Google Scholar]
  32. Miki S., Iwano M., Miki Y., Yamamoto M., Tang B., Yokokawa K., Sonoda T., Hirano T., Kishimoto T. Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett. 1989 Jul 3;250(2):607–610. doi: 10.1016/0014-5793(89)80805-1. [DOI] [PubMed] [Google Scholar]
  33. Miller A. D., Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol. 1986 Aug;6(8):2895–2902. doi: 10.1128/mcb.6.8.2895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Muraguchi A., Hirano T., Tang B., Matsuda T., Horii Y., Nakajima K., Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med. 1988 Feb 1;167(2):332–344. doi: 10.1084/jem.167.2.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Muraguchi A., Hirano T., Tang B., Matsuda T., Horii Y., Nakajima K., Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med. 1988 Feb 1;167(2):332–344. doi: 10.1084/jem.167.2.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nagai M., Irino S., Uda H., Ohtsu T., Tobinai K., Shimoyama M. Molecular genetic and immunohistochemical analyses of a case of multicentric Castleman's disease. Jpn J Clin Oncol. 1988 Jun;18(2):149–157. [PubMed] [Google Scholar]
  37. Nakajima K., Martínez-Maza O., Hirano T., Breen E. C., Nishanian P. G., Salazar-Gonzalez J. F., Fahey J. L., Kishimoto T. Induction of IL-6 (B cell stimulatory factor-2/IFN-beta 2) production by HIV. J Immunol. 1989 Jan 15;142(2):531–536. [PubMed] [Google Scholar]
  38. Nordan R. P., Potter M. A macrophage-derived factor required by plasmacytomas for survival and proliferation in vitro. Science. 1986 Aug 1;233(4763):566–569. doi: 10.1126/science.3726549. [DOI] [PubMed] [Google Scholar]
  39. Okada M., Kitahara M., Kishimoto S., Matsuda T., Hirano T., Kishimoto T. IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol. 1988 Sep 1;141(5):1543–1549. [PubMed] [Google Scholar]
  40. Prowse K. R., Baumann H. Interleukin-1 and interleukin-6 stimulate acute-phase protein production in primary mouse hepatocytes. J Leukoc Biol. 1989 Jan;45(1):55–61. doi: 10.1002/jlb.45.1.55. [DOI] [PubMed] [Google Scholar]
  41. Sehgal P. B., Helfgott D. C., Santhanam U., Tatter S. B., Clarick R. H., Ghrayeb J., May L. T. Regulation of the acute phase and immune responses in viral disease. Enhanced expression of the beta 2-interferon/hepatocyte-stimulating factor/interleukin 6 gene in virus-infected human fibroblasts. J Exp Med. 1988 Jun 1;167(6):1951–1956. doi: 10.1084/jem.167.6.1951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Suematsu S., Matsuda T., Aozasa K., Akira S., Nakano N., Ohno S., Miyazaki J., Yamamura K., Hirano T., Kishimoto T. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7547–7551. doi: 10.1073/pnas.86.19.7547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Takai Y., Wong G. G., Clark S. C., Burakoff S. J., Herrmann S. H. B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes. J Immunol. 1988 Jan 15;140(2):508–512. [PubMed] [Google Scholar]
  44. Ueno Y., Takano N., Kanegane H., Yokoi T., Yachie A., Miyawaki T., Taniguchi N. The acute phase nature of interleukin 6: studies in Kawasaki disease and other febrile illnesses. Clin Exp Immunol. 1989 Jun;76(3):337–342. [PMC free article] [PubMed] [Google Scholar]
  45. Waage A., Brandtzaeg P., Halstensen A., Kierulf P., Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med. 1989 Jan 1;169(1):333–338. doi: 10.1084/jem.169.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Walther Z., May L. T., Sehgal P. B. Transcriptional regulation of the interferon-beta 2/B cell differentiation factor BSF-2/hepatocyte-stimulating factor gene in human fibroblasts by other cytokines. J Immunol. 1988 Feb 1;140(3):974–977. [PubMed] [Google Scholar]
  47. Whitney J. B., 3rd Simplified typing of mouse hemoglobin (Hbb) phenotypes using cystamine. Biochem Genet. 1978 Aug;16(7-8):667–672. doi: 10.1007/BF00484723. [DOI] [PubMed] [Google Scholar]
  48. Wong G. G., Witek-Giannotti J. S., Temple P. A., Kriz R., Ferenz C., Hewick R. M., Clark S. C., Ikebuchi K., Ogawa M. Stimulation of murine hemopoietic colony formation by human IL-6. J Immunol. 1988 May 1;140(9):3040–3044. [PubMed] [Google Scholar]
  49. Wong P. M., Chung S. W., Nienhuis A. W. Retroviral transfer and expression of the interleukin-3 gene in hemopoietic cells. Genes Dev. 1987 Jun;1(4):358–365. doi: 10.1101/gad.1.4.358. [DOI] [PubMed] [Google Scholar]
  50. Yee C., Biondi A., Wang X. H., Iscove N. N., de Sousa J., Aarden L. A., Wong G. G., Clark S. C., Messner H. A., Minden M. D. A possible autocrine role for interleukin-6 in two lymphoma cell lines. Blood. 1989 Aug 1;74(2):798–804. [PubMed] [Google Scholar]
  51. Yokota T., Lee F., Rennick D., Hall C., Arai N., Mosmann T., Nabel G., Cantor H., Arai K. Isolation and characterization of a mouse cDNA clone that expresses mast-cell growth-factor activity in monkey cells. Proc Natl Acad Sci U S A. 1984 Feb;81(4):1070–1074. doi: 10.1073/pnas.81.4.1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Yoshizaki K., Matsuda T., Nishimoto N., Kuritani T., Taeho L., Aozasa K., Nakahata T., Kawai H., Tagoh H., Komori T. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood. 1989 Sep;74(4):1360–1367. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES