Transforming growth factor beta is a growth-inhibitory cytokine of B cell lymphoma in SIV-infected macaques

Cytokine dysregulation is accepted as one of the pivotal factors in the pat hogenesis of B cell lymphomas in HIV-positive patients. So far no data exis t on inhibitory cytokines in the regulatory network of HIV-associated B-NHL . Simian immunodeficiency virus (SIV)-infected macaques are a well-establis hed in vivo model of HIV infection in humans. We used this model for the id entification of TGF-beta as a growth-inhibitory cytokine of SIV-associated B cell lymphomas, Fifty-seven rhesus macaques were infected with SIVmac. Ni ne animals developed B cell lymphomas: eight with high-grade lymphomas of t he immunoblastic, centroblastic, and "Burkitt-like" type, and one with the centroblastic/centrocytic type according to the Kiel classification. Six of seven analyzed lymphomas were infected with the macaque EBV, herpes virus macaca mulatta (HVMM). The lymphomas and the SIV-associated B cell lymphoma cell line H50 were positive for transcription of the TGF-beta gene. Protei n expression and secretion of the active cytokine were proved by immunohist ochemistry and ELISA, H50 transcribed the TGF-beta type I and type II recep tor (R I/II), betaglycan, and endoglin, Furthermore, all primary lymphoma s amples tested were positive for receptor type I/II, transcription and prote in expression, TGF-beta induced reduction of cell viability by 67% (range, 50-84% and enhanced apoptosis by 69% (range, 33-111%) compared with the con trol. TGF-beta activity was blocked by a specific anti-TGF-beta antibody. T hus, TGF-beta fulfilled the criteria of a negative autocrine inhibitor in H 50, These data identify TGF-beta as a promising candidate as an inhibitory factor in the regulatory network of HIV-associated lymphomagenesis.