Tumor-necrosis factor-a （TNF-a）-driven nuclear factor-KB （NF-KB） activation and apoptosis are opposing pathways; the growing recognition of these conflicting roles of TNF-a is perplexing. Here, we show that inflam...Tumor-necrosis factor-a （TNF-a）-driven nuclear factor-KB （NF-KB） activation and apoptosis are opposing pathways; the growing recognition of these conflicting roles of TNF-a is perplexing. Here, we show that inflammation and apoptosis are time-phased events following TNF-a signaling and that emergence of suppressor of cytokine signaling 3 （SOCS3） expression limits the ongoing NF-KB activation and promotes apoptosis; further, we suggest an altered view of how inflammatory diseases are initiated and sustained. In vitro, TNF-a （50 ng/ml） induced granulocyte SOCS3 protein, inhibited nuclear accumulation of the p65NF-KB subunit and enhanced apoptosis, as shown by DNA laddering, annexin V positivity, and overexpression of caspase-3 and Bax in the late phase, whereas the early phase was marked by NF-KB activation. Conversely, SOCS3 knockdown by small interfering RNA （siRNA） inhibited granulocyte apoptosis and enhanced nuclear accumulation of p65 and 5＇ lipooxygenase expression in the late phase of TNF-a signaling. As apoptosis is associated with SOCS3 abundance, we suggest that these divergent TNF-a-driven events are time-phased, interconnected, opposing control mechanisms and one of the central features through which the immune system resolves pulmonary inflammation. Dysregulation may initiate mucosal inflammation, thus changing the landscape of asthma theraov.展开更多
文摘Tumor-necrosis factor-a （TNF-a）-driven nuclear factor-KB （NF-KB） activation and apoptosis are opposing pathways; the growing recognition of these conflicting roles of TNF-a is perplexing. Here, we show that inflammation and apoptosis are time-phased events following TNF-a signaling and that emergence of suppressor of cytokine signaling 3 （SOCS3） expression limits the ongoing NF-KB activation and promotes apoptosis; further, we suggest an altered view of how inflammatory diseases are initiated and sustained. In vitro, TNF-a （50 ng/ml） induced granulocyte SOCS3 protein, inhibited nuclear accumulation of the p65NF-KB subunit and enhanced apoptosis, as shown by DNA laddering, annexin V positivity, and overexpression of caspase-3 and Bax in the late phase, whereas the early phase was marked by NF-KB activation. Conversely, SOCS3 knockdown by small interfering RNA （siRNA） inhibited granulocyte apoptosis and enhanced nuclear accumulation of p65 and 5＇ lipooxygenase expression in the late phase of TNF-a signaling. As apoptosis is associated with SOCS3 abundance, we suggest that these divergent TNF-a-driven events are time-phased, interconnected, opposing control mechanisms and one of the central features through which the immune system resolves pulmonary inflammation. Dysregulation may initiate mucosal inflammation, thus changing the landscape of asthma theraov.
