Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1995 May 1;14(9):1932–1941. doi: 10.1002/j.1460-2075.1995.tb07185.x

Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice.

I Screpanti 1, L Romani 1, P Musiani 1, A Modesti 1, E Fattori 1, D Lazzaro 1, C Sellitto 1, S Scarpa 1, D Bellavia 1, G Lattanzio 1, et al.
PMCID: PMC398292  PMID: 7744000

Abstract

C/EBP beta is considered a key element of interleukin-6 (IL-6) signalling as well as an important transcriptional regulator of the IL-6 gene itself. We describe here how mice lacking C/EBP beta develop a pathology similar to mice overexpressing IL-6 and nearly identical to multicentric Castleman's disease in human patients, with marked splenomegaly, peripheral lymphadenopathy and enhanced haemopoiesis. Humoral, innate and cellular immunity are also profoundly distorted, as shown by the defective activation of splenic macrophages, the strong impairement of IL-12 production, the increased susceptibility to Candida albicans infection and the altered T-helper function. Our data show that C/EBP beta is crucial for the correct functional regulation and homeostatic control of haemopoietic and lymphoid compartments.

Full text

PDF
1941

Images in this article

Selected References

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

  1. Akira S., Isshiki H., Sugita T., Tanabe O., Kinoshita S., Nishio Y., Nakajima T., Hirano T., Kishimoto T. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990 Jun;9(6):1897–1906. doi: 10.1002/j.1460-2075.1990.tb08316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beck J. T., Hsu S. M., Wijdenes J., Bataille R., Klein B., Vesole D., Hayden K., Jagannath S., Barlogie B. Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med. 1994 Mar 3;330(9):602–605. doi: 10.1056/NEJM199403033300904. [DOI] [PubMed] [Google Scholar]
  3. Brandt S. J., Bodine D. M., Dunbar C. E., Nienhuis A. W. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest. 1990 Aug;86(2):592–599. doi: 10.1172/JCI114749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cao Z., Umek R. M., McKnight S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991 Sep;5(9):1538–1552. doi: 10.1101/gad.5.9.1538. [DOI] [PubMed] [Google Scholar]
  5. Cenci E., Romani L., Mencacci A., Spaccapelo R., Schiaffella E., Puccetti P., Bistoni F. Interleukin-4 and interleukin-10 inhibit nitric oxide-dependent macrophage killing of Candida albicans. Eur J Immunol. 1993 May;23(5):1034–1038. doi: 10.1002/eji.1830230508. [DOI] [PubMed] [Google Scholar]
  6. Cooper C., Johnson D., Roman C., Avitahl N., Tucker P., Calame K. The C/EBP family of transcriptional activators is functionally important for Ig VH promoter activity in vivo and in vitro. J Immunol. 1992 Nov 15;149(10):3225–3231. [PubMed] [Google Scholar]
  7. Descombes P., Chojkier M., Lichtsteiner S., Falvey E., Schibler U. LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev. 1990 Sep;4(9):1541–1551. doi: 10.1101/gad.4.9.1541. [DOI] [PubMed] [Google Scholar]
  8. Descombes P., Schibler U. A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell. 1991 Nov 1;67(3):569–579. doi: 10.1016/0092-8674(91)90531-3. [DOI] [PubMed] [Google Scholar]
  9. Fattori E., Della Rocca C., Costa P., Giorgio M., Dente B., Pozzi L., Ciliberto G. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood. 1994 May 1;83(9):2570–2579. [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. Gorski K., Carneiro M., Schibler U. Tissue-specific in vitro transcription from the mouse albumin promoter. Cell. 1986 Dec 5;47(5):767–776. doi: 10.1016/0092-8674(86)90519-2. [DOI] [PubMed] [Google Scholar]
  12. Hirano T., Akira S., Taga T., Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today. 1990 Dec;11(12):443–449. doi: 10.1016/0167-5699(90)90173-7. [DOI] [PubMed] [Google Scholar]
  13. Ihle J. N., Witthuhn B. A., Quelle F. W., Yamamoto K., Thierfelder W. E., Kreider B., Silvennoinen O. Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem Sci. 1994 May;19(5):222–227. doi: 10.1016/0968-0004(94)90026-4. [DOI] [PubMed] [Google Scholar]
  14. Isshiki H., Akira S., Sugita T., Nishio Y., Hashimoto S., Pawlowski T., Suematsu S., Kishimoto T. Reciprocal expression of NF-IL6 and C/EBP in hepatocytes: possible involvement of NF-IL6 in acute phase protein gene expression. New Biol. 1991 Jan;3(1):63–70. [PubMed] [Google Scholar]
  15. Kanagawa O., Vaupel B. A., Gayama S., Koehler G., Kopf M. Resistance of mice deficient in IL-4 to retrovirus-induced immunodeficiency syndrome (MAIDS) Science. 1993 Oct 8;262(5131):240–242. doi: 10.1126/science.8211142. [DOI] [PubMed] [Google Scholar]
  16. Kinoshita S., Akira S., Kishimoto T. A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1473–1476. doi: 10.1073/pnas.89.4.1473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  18. Lowenstein C. J., Alley E. W., Raval P., Snowman A. M., Snyder S. H., Russell S. W., Murphy W. J. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9730–9734. doi: 10.1073/pnas.90.20.9730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  20. Nakajima T., Kinoshita S., Sasagawa T., Sasaki K., Naruto M., Kishimoto T., Akira S. Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2207–2211. doi: 10.1073/pnas.90.6.2207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  22. Natsuka S., Akira S., Nishio Y., Hashimoto S., Sugita T., Isshiki H., Kishimoto T. Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood. 1992 Jan 15;79(2):460–466. [PubMed] [Google Scholar]
  23. Poli V., Balena R., Fattori E., Markatos A., Yamamoto M., Tanaka H., Ciliberto G., Rodan G. A., Costantini F. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 1994 Mar 1;13(5):1189–1196. doi: 10.1002/j.1460-2075.1994.tb06368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Poli V., Mancini F. P., Cortese R. IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell. 1990 Nov 2;63(3):643–653. doi: 10.1016/0092-8674(90)90459-r. [DOI] [PubMed] [Google Scholar]
  25. Puccetti P., Mencacci A., Cenci E., Spaccapelo R., Mosci P., Enssle K. H., Romani L., Bistoni F. Cure of murine candidiasis by recombinant soluble interleukin-4 receptor. J Infect Dis. 1994 Jun;169(6):1325–1331. doi: 10.1093/infdis/169.6.1325. [DOI] [PubMed] [Google Scholar]
  26. Robertson E., Bradley A., Kuehn M., Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature. 1986 Oct 2;323(6087):445–448. doi: 10.1038/323445a0. [DOI] [PubMed] [Google Scholar]
  27. Romani L., Mencacci A., Grohmann U., Mocci S., Mosci P., Puccetti P., Bistoni F. Neutralizing antibody to interleukin 4 induces systemic protection and T helper type 1-associated immunity in murine candidiasis. J Exp Med. 1992 Jul 1;176(1):19–25. doi: 10.1084/jem.176.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Romani L., Mencacci A., Tonnetti L., Spaccapelo R., Cenci E., Puccetti P., Wolf S. F., Bistoni F. IL-12 is both required and prognostic in vivo for T helper type 1 differentiation in murine candidiasis. J Immunol. 1994 Dec 1;153(11):5167–5175. [PubMed] [Google Scholar]
  29. Romani L., Mocci S., Bietta C., Lanfaloni L., Puccetti P., Bistoni F. Th1 and Th2 cytokine secretion patterns in murine candidiasis: association of Th1 responses with acquired resistance. Infect Immun. 1991 Dec;59(12):4647–4654. doi: 10.1128/iai.59.12.4647-4654.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Romani L., Puccetti P., Mencacci A., Cenci E., Spaccapelo R., Tonnetti L., Grohmann U., Bistoni F. Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice from challenge with Candida albicans. J Immunol. 1994 Apr 1;152(7):3514–3521. [PubMed] [Google Scholar]
  31. Scott L. M., Civin C. I., Rorth P., Friedman A. D. A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood. 1992 Oct 1;80(7):1725–1735. [PubMed] [Google Scholar]
  32. 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]
  33. Thomas K. R., Capecchi M. R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987 Nov 6;51(3):503–512. doi: 10.1016/0092-8674(87)90646-5. [DOI] [PubMed] [Google Scholar]
  34. Trautwein C., Caelles C., van der Geer P., Hunter T., Karin M., Chojkier M. Transactivation by NF-IL6/LAP is enhanced by phosphorylation of its activation domain. Nature. 1993 Aug 5;364(6437):544–547. doi: 10.1038/364544a0. [DOI] [PubMed] [Google Scholar]
  35. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. doi: 10.1016/0167-5699(93)90230-I. [DOI] [PubMed] [Google Scholar]
  36. 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 The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES