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.

Growth regulation of simian and human AIDS-related non-Hodgkin's lymphoma cell lines by TGF-β1 and IL-6

“…Using an immunoblastic SAIDS-NHL cell line shown to represent the original tumor mass (Figure 1), initial studies confirmed a previous report [20] that SAIDS-NHL cells may be sensitive to TGF-β1-mediated growth inhibition in a dose-dependent manner (Figure 2A). The marked sensitivity to growth inhibition by TGF-β1 suggested that a counteracting positive influence may be operative in SAIDS-NHL.…”

“…Based on the previous report of sensitivity of a single SAIDS-NHL-derived cell line to TGF-β1-mediated inhibition [20], an investigation was initiated to determine whether the finding could be recapitulated in LCL8664, a SAIDS-NHL-derived cell line from the Tulane National Primate Research Center characterized morphologically as immunoblastoid DLBCL [8]. LCL8664, like the original tumor, is of B-cell origin and is infected with rhesus lymphocryptovirus (RhLCV), the rhesus homologue of human EBV [7,9].…”

“…TGF-β was shown to reduce cell viability by 67% and to increase apoptosis by 69% (range, 33–111%). The authors concluded that TGF-β acts as a negative growth regulator of the lymphoma-derived cell line and, potentially, as an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis [20]. These findings were unexpected, given that (1) many cancers, including leukemias and other tumors of hematopoietic origin, typically develop resistance to TGF-β as a mechanism for progression [21-23], and (2) the majority of SAIDS-related lymphomas are infected with RhLCV, whose human-specific counterpart, EBV, is known to impart resistance to TGF-β inhibition in human lymphoblastoid cell lines [24,25].…”

Modelling the dynamics of HIV‐related non‐Hodgkin lymphomas in the presence of HIV treatment and chemotherapy

“…where f ∶ R n+1 → R n is analytic for ∈ R, x ∈ R n . Let x = x 0 ( ) be a class of equilibrium points of Equation 13, ie, f(x 0 ( ), ) = 0. We now set y = x − x 0 ( ),…”

“…8,9,12 Regarding the functions of the cytokines expressed in patients with NHL, TGF-acts as a negative growth regulator of the lymphoma-derived cell line and has been shown to be potentially an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis. 4,13 It has an immunosuppressive role, mediated predominantly by its effects on T cells and antigen-presenting cells, 14 thus favoring the growth of malignancies. As indicated by Kekow et al, 15 TGF-is likely to contribute to the deficit in T cell surveillance, which is of paramount importance in suppressing tumor growth.…”