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

Abstract

Transcription of the human tumor necrosis factor a (TNF-a) 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-a gene transcription, which can be blocked by the immunosuppressants cyclosporin A (CsA) and FK506. Here, TNF-a 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-a produced after stimulation was involved in B-cell proliferation since anti-TNF-a monoclonal antibody inhibited both anti-Ig-and anti-CD40-induced B-cell proliferative responses. Moreover, addition of TNF-a during stimulation resulted in augmentation of B-cell proliferation, which was also inhibited by anti-TNF-a monoclonal antibody. Although lymphotoxin a (LT-a) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-I8nmRNA is constitutively expressed in B cells. Thus, TNF-a 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-a in activated B cells implies a potential role for this cytokine in infection-related polyclonal B-cell expansion and in B-cell malignancies.

Human genetic factors related to susceptibility to mild malaria in Gabon

“…Hitherto TNF-␣ gene expression has not been related to any variation in cytokine production, thus the −238 and −308 polymorphisms may serve as markers for a functional polymorphism elsewhere in the TNF-␣ gene or in another immunologically relevant gene situated nearby. 12 TNF-␣ is also critical in the development of the humoral response as an autocrine B cell growth factor, 33 representing an important mediator of B cell regulation during several parasitic diseases including malaria. 34 In our study, the TNF −238 A allele was linked to high levels of plasma antibodies directed to peptides NTSDSQKE and LTPLEELYP from the MSA-2 and RAP-1 antigens of P. falciparum, respectively.…”

“…Firstly, a second polymorphism, TNF −376 A, which is frequently found in linkage disequilibrium with TNF −238 A, is related to enhanced secretion of TNF 11 and might be responsible for increased antigen-or T-cell-mediated B-cell stimulation and proliferation. 33 Alternatively, the TNF −238 A allele may preferentially induce TNF-␣ in its soluble rather than its membrane-bound form. These different forms of TNF-␣ bind to different TNF receptors named TNFR1 (soluble form) and TNFR2 (membrane-bound form).…”

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

“…25,26 Furthermore, the CD40L and IL-4 stimulation has been shown to promote transcription of the TNF-a gene and to increase B-cell growth. 27 It is reasonable to expect that as the proportion of these CD39 high B cells increases, so do levels of 5 0 -AMP and ADO they produce. Indeed, ADO produced by CD39 high B cells is likely to be responsible for suppression of activation and proliferation of CD4 C Teff in co-cultures of these lymphocyte populations (Fig.…”

Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks

“…The pathogenic significance of TNF has been demonstrated by the clinical efficacy of TNF blockade in the treatment of RA (6). Interestingly, TNF and LT␣ (also blocked by some anti-TNF drugs) may exert powerful direct and indirect influences over B cells (which express TNFR1 and TNFR2) and through B cells that may produce TNF and constitute the main source of LT␣ (7)(8)(9). Of note, in mice B cellborne LT␣ is critical for the development and maintenance of spleen and lymph node microarchitecture (10).…”