TUMOR-NECROSIS-FACTOR-ALPHA IS AN AUTOCRINE GROWTH-FACTOR FOR NORMAL HUMAN B-CELLS

Transcription of the human tumor necrosis factor alpha (TNF-alpha) gen e is one of the earliest events that occurs after stimulation of B or T cells via their antigen receptors. Antibody directed at surface immu noglobulin (anti-Ig) on B cells has previously been shown to induce a rapid burst of TNF-alpha gene transcription, which can be blocked by t he immunosuppressants cyclosporin A (CsA) and FK506. Here, TNF-alpha g ene transcription is shown also to be highly and rapidly induced in hu man B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analo gues 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-C D40-induced B-cell proliferative responses. Moreover, addition of TNF- alpha during stimulation resulted in augmentation of B-cell proliferat ion, which was also inhibited by anti-TNF-alpha monoclonal antibody. A lthough lymphotoxin alpha (LT-alpha) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-beta mRNA is constitutively expr essed in B cells. Thus, TNF-alpha is a necessary autocrine growth fact or for human B cells stimulated via two independent CsA-sensitive path ways and plays a role similar to that of interleukin 2 in T-cell proli feration. The autocrine nature of TNF-alpha in activated B cells impli es a potential role for this cytokine in infection-related polyclonal B-cell expansion and in B cell malignancies.