title: SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-α signaling.
abstract: Tumor-necrosis factor-α (TNF-α)-driven nuclear factor-κB (NF-κB) activation and apoptosis are opposing pathways; the growing recognition of these conflicting roles of TNF-α is perplexing. Here, we show that inflammation and apoptosis are time-phased events following TNF-α signaling and that emergence of suppressor of cytokine signaling 3 (SOCS3) expression limits the ongoing NF-κB activation and promotes apoptosis; further, we suggest an altered view of how inflammatory diseases are initiated and sustained. In vitro, TNF-α (50 ng/ml) induced granulocyte SOCS3 protein, inhibited nuclear accumulation of the p65NF-κB 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-κB 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-α signaling. As apoptosis is associated with SOCS3 abundance, we suggest that these divergent TNF-α-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.
authors.affiliation: Immunobiology Division, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Jasmeet Kaur
authors.initials: JK
authors.lastname: Chhabra
authors.affiliation: Department of Physics, Faculty of Science, Jadavpur University, Kolkata, India.
authors.forename: Brajadulal
authors.initials: B
authors.lastname: Chattopadhyay
authors.affiliation: Immunobiology Division, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Bhola Nath
authors.initials: BN
authors.lastname: Paul
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha
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