The Journal of Immunology, Vol 146, Issue 10 3462-3468, Copyright © 1991 by American Association of Immunologists

ARTICLES

IL-6 and tumor necrosis factor-alpha. Autocrine and paracrine cytokines involved in B cell function

P Rieckmann, F D'Alessandro, RP Nordan, AS Fauci and JH Kehrl
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.

IL-6 and TNF-alpha are synthesized and secreted by normal tonsillar B cells after stimulation with the polyclonal B cell activator Staphylococcus aureus Cowan strain 1 (SAC) and IL-2 as well as spontaneously by in vivo activated B cells from patients with hypergammaglobulinemia. Using specific neutralizing antibodies, both factors were shown to be involved in autocrine and/or paracrine regulation of B cell differentiation. IgG induced by SAC/IL-2 stimulation was reduced 73% with an anti-IL-6 antibody and 40% with an anti-TNF-alpha antibody. Similar effects of these antibodies were observed on the spontaneous in vitro IgG production by lymphoblastic B cells from six patients with hypergammaglobulinemia. Kinetic studies with SAC/IL-2-activated B cells revealed that the anti-TNF-alpha antibody must be present at the beginning of the culture to exert an effect on Ig production, whereas the anti-IL-6 antibody reduced Ig production even if added as late as day 3. This sequential action of TNF-alpha and IL-6 on B cell differentiation was reflected by different kinetics of release of these two cytokines into the supernatant of SAC/IL-2 activated B cells; TNF-alpha peaked at 24 h and IL-6 at 96 h after stimulation. In addition, it was shown that IL-6 production by in vitro-activated B cells was partially blocked by an anti-TNF-alpha antibody suggesting that TNF-alpha regulates IL-6 production in normal B cells via an autocrine pathway. We also investigated the effects of TGF-beta on TNF-alpha and IL-6 production by normal B cells. Although TGF-beta inhibited Ig production by in vitro-activated and in vivo- activated B cells, it did not inhibit the release of these cytokines from normal B cells. Furthermore, TGF-beta did not inhibit the induction of nuclear factor-IL-6 nor the expression of IL-6R on activated B cells. Thus, although the biologic effects of anti-IL-6 and TGF-beta on B cell Ig production are similar, their mechanisms of actions appear to be distinct.

This article has been cited by other articles:

				A. L. Peters, R. M. Plenge, R. R. Graham, D. M. Altshuler, K. L. Moser, P. M. Gaffney, and G. A. Bishop A novel polymorphism of the human CD40 receptor with enhanced function Blood, September 1, 2008; 112(5): 1863 - 1871. [Abstract] [Full Text] [PDF]

				D. T. Avery, V. L. Bryant, C. S. Ma, R. de Waal Malefyt, and S. G. Tangye IL-21-Induced Isotype Switching to IgG and IgA by Human Naive B Cells Is Differentially Regulated by IL-4 J. Immunol., August 1, 2008; 181(3): 1767 - 1779. [Abstract] [Full Text] [PDF]

				D. R. Hodge, W. Xiao, B. Peng, J. C. Cherry, D. J. Munroe, and W. L. Farrar Enforced Expression of Superoxide Dismutase 2/Manganese Superoxide Dismutase Disrupts Autocrine Interleukin-6 Stimulation in Human Multiple Myeloma Cells and Enhances Dexamethasone-Induced Apoptosis Cancer Res., July 15, 2005; 65(14): 6255 - 6263. [Abstract] [Full Text] [PDF]

				Q. Xu, E. Goleva, L.-S. Ou, L.-B. Li, and D. Y. M. Leung CD56+ Cells Induce Steroid Resistance in B Cells Exposed to IL-15 J. Immunol., June 1, 2004; 172(11): 7110 - 7115. [Abstract] [Full Text] [PDF]

				G. A. Bishop, B. S. Hostager, and K. D. Brown Mechanisms of TNF receptor-associated factor (TRAF) regulation in B lymphocytes J. Leukoc. Biol., July 1, 2002; 72(1): 19 - 23. [Abstract] [Full Text] [PDF]

				B. S. Hostager and G. A. Bishop Role of TNF Receptor-Associated Factor 2 in the Activation of IgM Secretion by CD40 and CD120b J. Immunol., April 1, 2002; 168(7): 3318 - 3322. [Abstract] [Full Text] [PDF]

				I. R. Blanca, E. W. Bere, H. A. Young, and J. R. Ortaldo Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5+ B Cells J. Immunol., December 1, 2001; 167(11): 6132 - 6139. [Abstract] [Full Text] [PDF]

				J. Hulkkonen, M. Pertovaara, J. Antonen, A. Pasternack, and M. Hurme Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL6 gene in primary Sjogren's syndrome and correlate with the clinical manifestations of the disease Rheumatology, June 1, 2001; 40(6): 656 - 661. [Abstract] [Full Text] [PDF]

				G. A. Bishop, Y. Hsing, B. S. Hostager, S. V. Jalukar, L. M. Ramirez, and M. A. Tomai Molecular Mechanisms of B Lymphocyte Activation by the Immune Response Modifier R-848 J. Immunol., November 15, 2000; 165(10): 5552 - 5557. [Abstract] [Full Text] [PDF]

				M. Rowley, P. Liu, and B. Van Ness Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan Blood, November 1, 2000; 96(9): 3175 - 3180. [Abstract] [Full Text] [PDF]

				G. R. Hill, T. Teshima, V. I. Rebel, O. I. Krijanovski, K. R. Cooke, Y. S. Brinson, and J. L. M. Ferrara The p55 TNF-{alpha} Receptor Plays a Critical Role in T Cell Alloreactivity J. Immunol., January 15, 2000; 164(2): 656 - 663. [Abstract] [Full Text] [PDF]

				K. Watson, N. J. Gooderham, D. S. Davies, and R. J. Edwards Nucleosomes Bind to Cell Surface Proteoglycans J. Biol. Chem., July 30, 1999; 274(31): 21707 - 21713. [Abstract] [Full Text] [PDF]

				J. Punnonen, B. G. Cocks, J. M. Carballido, B. Bennett, D. Peterson, G. Aversa, and J. E. d. Vries Soluble and Membrane-bound Forms of Signaling Lymphocytic Activation Molecule (SLAM) Induce Proliferation and Ig Synthesis by Activated Human B Lymphocytes J. Exp. Med., March 17, 1997; 185(6): 993 - 1004. [Abstract] [Full Text] [PDF]