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

Abstract

Cytokine dysregulation is accepted as one of the pivotal factors in the pathogenesis of B cell lymphomas in HIV-positive patients. So far no data exist on inhibitory cytokines in the regulatory network of HIV-associated B-NHL. Simian immunodeficiency virus (SIV)-infected macaques are a well-established in vivo model of HIV infection in humans. We used this model for the identification of TGF-beta as a growth-inhibitory cytokine of SIV-associated B cell lymphomas. Fifty-seven rhesus macaques were infected with SIVmac. Nine animals developed B cell lymphomas: eight with high-grade lymphomas of the 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. Protein expression and secretion of the active cytokine were proved by immunohistochemistry and ELISA. H50 transcribed the TGF-beta type I and type II receptor (R I/II), betaglycan, and endoglin. Furthermore, all primary lymphoma samples tested were positive for receptor type I/II transcription and protein expression. TGF-beta induced reduction of cell viability by 67% (range, 50-84% and enhanced apoptosis by 69% (range, 33-111%) compared with the control. TGF-beta activity was blocked by a specific anti-TGF-beta antibody. Thus, TGF-beta fulfilled the criteria of a negative autocrine inhibitor in H50. These data identify TGF-beta as a promising candidate as an inhibitory factor in the regulatory network of HIV-associated lymphomagenesis.