RESUMO
ABT-263 and its structural analogues ABT-199 and ABT-737 inhibit B-cell lymphoma 2 (Bcl-2), BCL2L1 long isoform (Bcl-xL) and BCL2L2 (Bcl-w) proteins and promote cancer cell death. Here, we show that at non-cytotoxic concentrations, these small molecules accelerate the deaths of non-cancerous cells infected with influenza A virus (IAV) or other viruses. In particular, we demonstrate that ABT-263 altered Bcl-xL interactions with Bcl-2 antagonist of cell death (Bad), Bcl-2-associated X protein (Bax), uveal autoantigen with coiled-coil domains and ankyrin repeats protein (UACA). ABT-263 thereby activated the caspase-9-mediated mitochondria-initiated apoptosis pathway, which, together with the IAV-initiated caspase-8-mediated apoptosis pathway, triggered the deaths of IAV-infected cells. Our results also indicate that Bcl-xL, Bcl-2 and Bcl-w interact with pattern recognition receptors (PRRs) that sense virus constituents to regulate cellular apoptosis. Importantly, premature killing of IAV-infected cells by ABT-263 attenuated the production of key pro-inflammatory and antiviral cytokines. The imbalance in cytokine production was also observed in ABT-263-treated IAV-infected mice, which resulted in an inability of the immune system to clear the virus and eventually lowered the survival rates of infected animals. Thus, the results suggest that the chemical inhibition of Bcl-xL, Bcl-2 and Bcl-w could potentially be hazardous for cancer patients with viral infections.
Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/biossíntese , Modelos Animais de Doenças , Vírus da Influenza A/fisiologia , Macrófagos/metabolismo , Camundongos , Neoplasias/patologia , Neoplasias/virologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/patologiaRESUMO
In the present report, we studied the role of the stromal-derived cytokine interleukin-7 (IL-7) in the IL-2-gene regulation in activated T lymphocytes. Production of IL-2 requires the formation of transcription factors involved in the IL-2-gene regulation. T-cell receptor (TCR)/CD3 engagement results in the activation of nuclear factor of activated T cells (NFAT), activator protein-1 (AP-1), and nuclear factor kappaB (NFkappaB), whereas the CD28 responsive complex (CD28RC) is activated in response to the CD28 signal. Costimulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with IL-7 induces a fivefold enhanced IL-2-mRNA accumulation and a 2.5-fold enhanced protein secretion. The IL-2-gene transcription rate is increased 3.4-fold, indicating that the effect of IL-7 is in part mediated at the transcriptional level. The molecular mechanisms underlying the IL-7 effect involve the upregulation of the DNA binding activity of NFAT (60%) and AP-1 (120%), without affecting the activities of NFkappaB and CD28RC, which was confirmed by transfection assays. We also show that the IL-7-induced enhancement of the AP-1-DNA binding activity is not cyclosporin A-sensitive. Since AP-1 is part of the NFAT complex, we conclude that the IL-7-signaling pathway is involved in the activation of the fos and jun proteins of which AP-1 consists.