Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells.
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.
Boussiotis
V A
VA
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA.
Nadler
L M
LM
Strominger
J L
JL
Goldfeld
A E
AE
D015703:Antigens, CD / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D019013:CD40 Antigens; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D012016:Reference Values; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D002148:Calmodulin-Binding Proteins; D006133:Growth Substances; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases