TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

Abstract

The role of TRAF2 and TRAF5 in TNFα-induced NF-κB activation has become complicated owing to the accumulation of conflicting data. Here, we report that 7-day-old TRAF2-knockout (KO) and TRAF2 TRAF5 double KO (TRAF2/5-DKO) mice exhibit enhanced canonical IκB kinase (IKK) and caspase-8 activation in spleen and liver, and that subsequent knockout of TNFα suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5-DKO cells, TNFα-induced immediate IKK activation is impaired, whereas delayed IKK activation occurs normally; as such, owing to elevated basal and TNFα-induced delayed IKK activation, TNFα stimulation leads to significantly increased induction of a subset of NF-κB-dependent genes in these cells. In line with this, both TRAF2 KO and TRAF2/5-DKO mice succumb to a sublethal dose of TNFα owing to increased expression of NF-κB target genes, diarrhea and bradypnea. Notably, depletion of IAP1 and IAP2 (also known as BIRC2 and BIRC3, respectively) also results in elevated basal IKK activation that is independent of autocrine TNFα production and that impairs TNFα-induced immediate IKK activation. These data reveal that TRAF2, IAP1 and IAP2, but not TRAF5, cooperatively regulate basal and TNFα-induced immediate IKK activation.

Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

“…TRAF2 interacts with TNF receptors and functions as a mediator of the anti-apoptotic signals emanated from these receptors 52 . TRAF2 downregulation might activate NF-kB and pro-inflammatory events of TNF-α 53 .…”

A data-driven computational model enables integrative and mechanistic characterization of dynamic macrophage polarization

“… (A) IκB expression ( Suzuki et al., 2002 ) and NF-κB activation ( Hu et al., 2005 ) in response to IL-1β. (B–D) (B) TNFα can induce activation of IKK/IκB/NF-κB axis ( Zhang et al., 2016 ; Etemadi et al., 2015 ; Lo et al., 2011 ), (C) MAPKs ( Ermolaeva et al., 2008 ), and (D) AP-1 ( Yarilina et al., 2011 ). (E–G) (E) Both IL-1β (left) and TNFα (right) can induce A20 ( Hu et al., 2014 ); (F and G) both IL-1β and TNFα can induce SOCS3 ( Wong et al., 2006 ; Ehlting et al., 2007 ).…”

“… (B–D) (B) TNFα can induce activation of IKK/IκB/NF-κB axis ( Zhang et al., 2016 ; Etemadi et al., 2015 ; Lo et al., 2011 ), (C) MAPKs ( Ermolaeva et al., 2008 ), and (D) AP-1 ( Yarilina et al., 2011 ). …”

“…The three pro-inflammatory drivers in the model, IL-1b, TNFa, and IFNg, are known to induce macrophage expression and secretion of an array of typical M1 markers: themselves such as IL-1b and TNFa (Figures 3A, and NF-kB activation in response to IL-1b. (B-D) (B) TNFa can induce activation of IKK/IkB/NF-kB axis (Zhang et al, 2016;Etemadi et al, 2015;, (C) MAPKs (Ermolaeva et al, 2008), and (D) AP-1 (Yarilina et al, 2011). (E-G) (E) Both IL-1b (left) and TNFa (right) can induce A20 (Hu et al, 2014); (F and G) both IL-1b and TNFa can induce SOCS3 (Wong et al, 2006;Ehlting et al, 2007).…”

Differential expression of death receptors, their ligands and adaptors as molecular signatures of neuropathologies in a mouse model of prion disease

“…However, cells lacking TRAF2 expression are compromised in TNFα-mediated JNK activation but partially de cient in NFκB activation [78,79] suggesting TRADD-TRAF2 has more cell survival function than in ammation. In this report, TRAF2 expression is decreased in prion-diseased mice brains.…”