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

Abstract

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