SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-? signaling.

ABSTRACT: Tumor-necrosis factor-? (TNF-?)-driven nuclear factor-?B (NF-?B) activation and apoptosis are opposing pathways; the growing recognition of these conflicting roles of TNF-? is perplexing. Here, we show that inflammation and apoptosis are time-phased events following TNF-? signaling and that emergence of suppressor of cytokine signaling 3 (SOCS3) expression limits the ongoing NF-?B activation and promotes apoptosis; further, we suggest an altered view of how inflammatory diseases are initiated and sustained. In vitro, TNF-? (50 ng/ml) induced granulocyte SOCS3 protein, inhibited nuclear accumulation of the p65NF-?B 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-?B 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-? signaling. As apoptosis is associated with SOCS3 abundance, we suggest that these divergent TNF-?-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 therapy.

SUBMITTER: Chhabra JK 

PROVIDER: S-EPMC4076751 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature