Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Jul 19;91(15):7007–7011. doi: 10.1073/pnas.91.15.7007

Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells.

V A Boussiotis 1, L M Nadler 1, J L Strominger 1, A E Goldfeld 1
PMCID: PMC44327  PMID: 7518925

Abstract

Transcription of the human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest events that occurs after stimulation of B or T cells via their antigen receptors. Antibody directed at surface immunoglobulin (anti-Ig) on B cells has previously been shown to induce a rapid burst of TNF-alpha gene transcription, which can be blocked by the immunosuppressants cyclosporin A (CsA) and FK506. Here, TNF-alpha gene transcription is shown also to be highly and rapidly induced in human B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analogues that block calcineurin phosphatase activity. Endogenous TNF-alpha produced after stimulation was involved in B-cell proliferation since anti-TNF-alpha monoclonal antibody inhibited both anti-Ig- and anti-CD40-induced B-cell proliferative responses. Moreover, addition of TNF-alpha during stimulation resulted in augmentation of B-cell proliferation, which was also inhibited by anti-TNF-alpha monoclonal antibody. Although lymphotoxin alpha (LT-alpha) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-beta mRNA is constitutively expressed in B cells. Thus, TNF-alpha is a necessary autocrine growth factor for human B cells stimulated via two independent CsA-sensitive pathways and plays a role similar to that of interleukin 2 in T-cell proliferation. The autocrine nature of TNF-alpha in activated B cells implies a potential role for this cytokine in infection-related polyclonal B-cell expansion and in B-cell malignancies.

Full text

PDF
7007

Images in this article

7008Image
on p.7008
7010Image
on p.7010

Selected References

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

  1. Abken H., Fluck J., Willecke K. Four cell-secreted cytokines act synergistically to maintain long term proliferation of human B cell lines in vitro. J Immunol. 1992 Oct 15;149(8):2785–2794. [PubMed] [Google Scholar]
  2. Andersson U., Adolf G., Dohlsten M., Möller G., Sjögren H. O. Characterization of individual tumor necrosis factor alpha-and beta-producing cells after polyclonal T cell activation. J Immunol Methods. 1989 Oct 24;123(2):233–240. doi: 10.1016/0022-1759(89)90227-5. [DOI] [PubMed] [Google Scholar]
  3. Armitage R. J., Fanslow W. C., Strockbine L., Sato T. A., Clifford K. N., Macduff B. M., Anderson D. M., Gimpel S. D., Davis-Smith T., Maliszewski C. R. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992 May 7;357(6373):80–82. doi: 10.1038/357080a0. [DOI] [PubMed] [Google Scholar]
  4. Aversa G., Punnonen J., de Vries J. E. The 26-kD transmembrane form of tumor necrosis factor alpha on activated CD4+ T cell clones provides a costimulatory signal for human B cell activation. J Exp Med. 1993 Jun 1;177(6):1575–1585. doi: 10.1084/jem.177.6.1575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boussiotis V. A., Freeman G. J., Gray G., Gribben J., Nadler L. M. B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance. J Exp Med. 1993 Nov 1;178(5):1753–1763. doi: 10.1084/jem.178.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boussiotis V. A., Freeman G. J., Gribben J. G., Daley J., Gray G., Nadler L. M. Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11059–11063. doi: 10.1073/pnas.90.23.11059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brockhaus M., Schoenfeld H. J., Schlaeger E. J., Hunziker W., Lesslauer W., Loetscher H. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3127–3131. doi: 10.1073/pnas.87.8.3127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Browning J. L., Ngam-ek A., Lawton P., DeMarinis J., Tizard R., Chow E. P., Hession C., O'Brine-Greco B., Foley S. F., Ware C. F. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell. 1993 Mar 26;72(6):847–856. doi: 10.1016/0092-8674(93)90574-a. [DOI] [PubMed] [Google Scholar]
  9. Dumont F. J., Staruch M. J., Koprak S. L., Melino M. R., Sigal N. H. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol. 1990 Jan 1;144(1):251–258. [PubMed] [Google Scholar]
  10. Estrov Z., Kurzrock R., Pocsik E., Pathak S., Kantarjian H. M., Zipf T. F., Harris D., Talpaz M., Aggarwal B. B. Lymphotoxin is an autocrine growth factor for Epstein-Barr virus-infected B cell lines. J Exp Med. 1993 Mar 1;177(3):763–774. doi: 10.1084/jem.177.3.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Foa R., Massaia M., Cardona S., Tos A. G., Bianchi A., Attisano C., Guarini A., di Celle P. F., Fierro M. T. Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease. Blood. 1990 Jul 15;76(2):393–400. [PubMed] [Google Scholar]
  12. Goeddel D. V., Aggarwal B. B., Gray P. W., Leung D. W., Nedwin G. E., Palladino M. A., Patton J. S., Pennica D., Shepard H. M., Sugarman B. J. Tumor necrosis factors: gene structure and biological activities. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):597–609. doi: 10.1101/sqb.1986.051.01.072. [DOI] [PubMed] [Google Scholar]
  13. Goldfeld A. E., Birch-Limberger K., Schooley R. T., Walker B. D. HIV-1 infection does not induce tumor necrosis factor-alpha or interferon-beta gene transcription. J Acquir Immune Defic Syndr. 1991;4(1):41–47. [PubMed] [Google Scholar]
  14. Goldfeld A. E., Doyle C., Maniatis T. Human tumor necrosis factor alpha gene regulation by virus and lipopolysaccharide. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9769–9773. doi: 10.1073/pnas.87.24.9769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goldfeld A. E., Flemington E. K., Boussiotis V. A., Theodos C. M., Titus R. G., Strominger J. L., Speck S. H. Transcription of the tumor necrosis factor alpha gene is rapidly induced by anti-immunoglobulin and blocked by cyclosporin A and FK506 in human B cells. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12198–12201. doi: 10.1073/pnas.89.24.12198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goldfeld A. E., Maniatis T. Coordinate viral induction of tumor necrosis factor alpha and interferon beta in human B cells and monocytes. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1490–1494. doi: 10.1073/pnas.86.5.1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goldfeld A. E., McCaffrey P. G., Strominger J. L., Rao A. Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor alpha gene promoter. J Exp Med. 1993 Oct 1;178(4):1365–1379. doi: 10.1084/jem.178.4.1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goldfeld A. E., Strominger J. L., Doyle C. Human tumor necrosis factor alpha gene regulation in phorbol ester stimulated T and B cell lines. J Exp Med. 1991 Jul 1;174(1):73–81. doi: 10.1084/jem.174.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gordon J. R., Galli S. J. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature. 1990 Jul 19;346(6281):274–276. doi: 10.1038/346274a0. [DOI] [PubMed] [Google Scholar]
  20. Gordon J., Millsum M. J., Guy G. R., Ledbetter J. A. Synergistic interaction between interleukin 4 and anti-Bp50 (CDw40) revealed in a novel B cell restimulation assay. Eur J Immunol. 1987 Oct;17(10):1535–1538. doi: 10.1002/eji.1830171026. [DOI] [PubMed] [Google Scholar]
  21. Gribben J. G., Freedman A. s., Woo S. D., Blake K., Shu R. S., Freeman G., Longtine J. A., Pinkus G. S., Nadler L. M. All advanced stage non-Hodgkin's lymphomas with a polymerase chain reaction amplifiable breakpoint of bcl-2 have residual cells containing the bcl-2 rearrangement at evaluation and after treatment. Blood. 1991 Dec 15;78(12):3275–3280. [PubMed] [Google Scholar]
  22. Hollenbaugh D., Grosmaire L. S., Kullas C. D., Chalupny N. J., Braesch-Andersen S., Noelle R. J., Stamenkovic I., Ledbetter J. A., Aruffo A. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 1992 Dec;11(12):4313–4321. doi: 10.1002/j.1460-2075.1992.tb05530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jelinek D. F., Lipsky P. E. Enhancement of human B cell proliferation and differentiation by tumor necrosis factor-alpha and interleukin 1. J Immunol. 1987 Nov 1;139(9):2970–2976. [PubMed] [Google Scholar]
  24. Kehrl J. H., Alvarez-Mon M., Delsing G. A., Fauci A. S. Lymphotoxin is an important T cell-derived growth factor for human B cells. Science. 1987 Nov 20;238(4830):1144–1146. doi: 10.1126/science.3500512. [DOI] [PubMed] [Google Scholar]
  25. Kehrl J. H., Miller A., Fauci A. S. Effect of tumor necrosis factor alpha on mitogen-activated human B cells. J Exp Med. 1987 Sep 1;166(3):786–791. doi: 10.1084/jem.166.3.786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kimoto H., Shirasawa T., Taniguchi M., Takemori T. B cell precursors are present in the thymus during early development. Eur J Immunol. 1989 Jan;19(1):97–104. doi: 10.1002/eji.1830190116. [DOI] [PubMed] [Google Scholar]
  27. Kinkhabwala M., Sehajpal P., Skolnik E., Smith D., Sharma V. K., Vlassara H., Cerami A., Suthanthiran M. A novel addition to the T cell repertory. Cell surface expression of tumor necrosis factor/cachectin by activated normal human T cells. J Exp Med. 1990 Mar 1;171(3):941–946. doi: 10.1084/jem.171.3.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Klaus G. G. Cyclosporine-sensitive and cyclosporine-insensitive modes of B cell stimulation. Transplantation. 1988 Aug;46(2 Suppl):11S–14S. doi: 10.1097/00007890-198808001-00002. [DOI] [PubMed] [Google Scholar]
  29. Kriegler M., Perez C., DeFay K., Albert I., Lu S. D. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988 Apr 8;53(1):45–53. doi: 10.1016/0092-8674(88)90486-2. [DOI] [PubMed] [Google Scholar]
  30. Liu J., Albers M. W., Wandless T. J., Luan S., Alberg D. G., Belshaw P. J., Cohen P., MacKintosh C., Klee C. B., Schreiber S. L. Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry. 1992 Apr 28;31(16):3896–3901. doi: 10.1021/bi00131a002. [DOI] [PubMed] [Google Scholar]
  31. Liu J. FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol Today. 1993 Jun;14(6):290–295. doi: 10.1016/0167-5699(93)90048-P. [DOI] [PubMed] [Google Scholar]
  32. Macchia D., Almerigogna F., Parronchi P., Ravina A., Maggi E., Romagnani S. Membrane tumour necrosis factor-alpha is involved in the polyclonal B-cell activation induced by HIV-infected human T cells. Nature. 1993 Jun 3;363(6428):464–466. doi: 10.1038/363464a0. [DOI] [PubMed] [Google Scholar]
  33. Noelle R. J., Roy M., Shepherd D. M., Stamenkovic I., Ledbetter J. A., Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550–6554. doi: 10.1073/pnas.89.14.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Peters P. M., Ortaldo J. R., Shalaby M. R., Svedersky L. P., Nedwin G. E., Bringman T. S., Hass P. E., Aggarwal B. B., Herberman R. B., Goeddel D. V. Natural killer-sensitive targets stimulate production of TNF-alpha but not TNF-beta (lymphotoxin) by highly purified human peripheral blood large granular lymphocytes. J Immunol. 1986 Oct 15;137(8):2592–2598. [PubMed] [Google Scholar]
  35. Ransom J. T., Chen M., Sandoval V. M., Pasternak J. A., Digiusto D., Cambier J. C. Increased plasma membrane permeability to Ca2+ in anti-Ig-stimulated B lymphocytes is dependent on activation of phosphoinositide hydrolysis. J Immunol. 1988 May 1;140(9):3150–3155. [PubMed] [Google Scholar]
  36. Ren C. L., Morio T., Fu S. M., Geha R. S. Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2. J Exp Med. 1994 Feb 1;179(2):673–680. doi: 10.1084/jem.179.2.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rousset F., Garcia E., Banchereau J. Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J Exp Med. 1991 Mar 1;173(3):705–710. doi: 10.1084/jem.173.3.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rubin B. Y., Anderson S. L., Sullivan S. A., Williamson B. D., Carswell E. A., Old L. J. Nonhematopoietic cells selected for resistance to tumor necrosis factor produce tumor necrosis factor. J Exp Med. 1986 Oct 1;164(4):1350–1355. doi: 10.1084/jem.164.4.1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schreiber S. L., Crabtree G. R. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136–142. doi: 10.1016/0167-5699(92)90111-J. [DOI] [PubMed] [Google Scholar]
  40. Shalaby M. R., Sundan A., Loetscher H., Brockhaus M., Lesslauer W., Espevik T. Binding and regulation of cellular functions by monoclonal antibodies against human tumor necrosis factor receptors. J Exp Med. 1990 Nov 1;172(5):1517–1520. doi: 10.1084/jem.172.5.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Steffen M., Ottmann O. G., Moore M. A. Simultaneous production of tumor necrosis factor-alpha and lymphotoxin by normal T cells after induction with IL-2 and anti-T3. J Immunol. 1988 Apr 15;140(8):2621–2624. [PubMed] [Google Scholar]
  42. Sung S. S., Bjorndahl J. M., Wang C. Y., Kao H. T., Fu S. M. Production of tumor necrosis factor/cachectin by human T cell lines and peripheral blood T lymphocytes stimulated by phorbol myristate acetate and anti-CD3 antibody. J Exp Med. 1988 Mar 1;167(3):937–953. doi: 10.1084/jem.167.3.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sung S. S., Jung L. K., Walters J. A., Chen W., Wang C. Y., Fu S. M. Production of tumor necrosis factor/cachectin by human B cell lines and tonsillar B cells. J Exp Med. 1988 Nov 1;168(5):1539–1551. doi: 10.1084/jem.168.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Turner M., Feldmann M. Comparison of patterns of expression of tumour necrosis factor, lymphotoxin and interleukin-6 mRNA. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1144–1151. doi: 10.1016/s0006-291x(88)81347-0. [DOI] [PubMed] [Google Scholar]
  45. Uckun F. M., Schieven G. L., Dibirdik I., Chandan-Langlie M., Tuel-Ahlgren L., Ledbetter J. A. Stimulation of protein tyrosine phosphorylation, phosphoinositide turnover, and multiple previously unidentified serine/threonine-specific protein kinases by the Pan-B-cell receptor CD40/Bp50 at discrete developmental stages of human B-cell ontogeny. J Biol Chem. 1991 Sep 15;266(26):17478–17485. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES