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

The role of TRAF2 and TRAF5 in TNF alpha-induced NF-kappa B 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 I kappa B kinase (IKK) and caspase-8 activation in spleen and liver, and that subsequent knockout of TNF alpha suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5-DKO cells, TNF alpha-induced immediate IKK activation is impaired, whereas delayed IKK activation occurs normally; as such, owing to elevated basal and TNF alpha-induced delayed IKK activation, TNFa stimulation leads to significantly increased induction of a subset of NF-kappa B-dependent genes in these cells. In line with this, both TRAF2 KO and TRAF2/5-DKO mice succumb to a sublethal dose of TNFa owing to increased expression of NF-kappa B 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 TNFa production and that impairs TNF alpha-induced immediate IKK activation. These data reveal that TRAF2, IAP1 and IAP2, but not TRAF5, cooperatively regulate basal and TNF alpha-induced immediate IKK activation.