Abstract
BackgroundAIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque consequent to infection with simian immunodeficiency virus. A recent study of SAIDS-NHL demonstrated a lymphoma-derived cell line to be sensitive to the growth inhibitory effects of the ubiquitous cytokine, transforming growth factor-beta (TGF-beta). The authors concluded that TGF-beta 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. The present study was conducted to assess whether other SAIDS-NHL and AIDS-NHL cell lines are similarly sensitive to the growth inhibitory effects of TGF-beta, and to test the hypothesis that interleukin-6 (IL-6) may represent a counteracting positive influence in their growth regulation.MethodsGrowth stimulation or inhibition in response to cytokine treatment was quantified using trypan blue exclusion or colorimetric MTT assay. Intracellular flow cytometry was used to analyze the activation of signaling pathways and to examine the expression of anti-apoptotic proteins and distinguishing hallmarks of AIDS-NHL subclass. Apoptosis was quantified by flow cytometric analysis of cell populations with sub-G1 DNA content and by measuring activated caspase-3.ResultsResults confirmed the sensitivity of LCL8664, an immunoblastic SAIDS-NHL cell line, to TGF-beta1-mediated growth inhibition, and further demonstrated the partial rescue by simultaneous treatment with IL-6. IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways. By comparison, human AIDS-NHL cell lines differed in their responsiveness to TGF-beta1 and IL-6. Analysis of a recently derived AIDS-NHL cell line, UMCL01-101, indicated that it represents immunoblastic AIDS-DLCBL. Like LCL-8664, UMCL01-101 was sensitive to TGF-beta1-mediated inhibition, rescued partially by IL-6, and demonstrated rapid STAT3 activation following IL-6 treatment even in the presence of TGF-beta1.ConclusionThese studies indicate that the sensitivity of immunoblastic AIDS- or SAIDS-DLBCL to TGF-beta1-mediated growth inhibition may be overcome through the stimulation of proliferative and anti-apoptotic signals by IL-6, particularly through the rapid activation of STAT3.
Highlights
AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals
Studies showed that IL-6 rescues LCL8664 cells, at least partially, from TGF-β1mediated growth inhibition (Figure 2B), and that signal transducer and activator of transcription-3 (STAT3) activation occurs rapidly after IL-6 treatment even in the presence of TGF-β1 (Figure 3)
The rapid activation of STAT3 signaling pathways may explain the ability of IL-6 to rescue cells from TGF-β1-mediated growth inhibition, since STAT3 is known to mediate proiliferative and antiapoptotic signaling in normal and tumor cells [39,40]
Summary
AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque consequent to infection with simian immunodeficiency virus. AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer (following Kaposi's sarcoma) associated with AIDS, and is the cause of death in approximately 16% of HIV-infected individuals [1,2]. Experimental analysis of AIDS-NHL pathogenesis has been facilitated by the availability of an excellent animal model for human AIDS, i.e., Simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque (Macaca mulatta) consequent to infection with simian immunodeficiency virus (SIV). SAIDS-related non-Hodgkin's lymphoma (SAIDSNHL) occurs in the SIV-infected rhesus macaque with an incidence approximating human AIDS-NHL [6,7]. The tumors are widely disseminated in anatomic distribution involving extranodal sites, most frequently the gastrointestinal tract, the genitourinary tract and the heart [6,7]
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