Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1α-Mediated NF-κB Activation and Down-Regulation of TRAF2 Expression

Abstract

NF-B is critical for determining cellular sensitivity to apoptotic stimuli by regulating both mitochondrial and death receptor apoptotic pathways. The endoplasmic reticulum (ER) emerges as a new apoptotic signaling initiator. However, the mechanism by which ER stress activates NF-B and its role in regulation of ER stress-induced cell death are largely unclear. Here, we report that, in response to ER stress, IKK forms a complex with IRE1␣ through the adapter protein TRAF2. ER stress-induced NF-B activation is impaired in IRE1␣ knockdown cells and IRE1␣ ؊/؊ MEFs. We found, however, that inhibiting NF-B significantly decreased ER stress-induced cell death in a caspase-8-dependent manner. Gene expression analysis revealed that ER stress-induced expression of tumor necrosis factor alpha (TNF-␣) was IRE1␣ and NF-B dependent. Blocking TNF receptor 1 signaling significantly inhibited ER stress-induced cell death. Further studies suggest that ER stress induces down-regulation of TRAF2 expression, which impairs TNF-␣-induced activation of NF-B and c-Jun N-terminal kinase and turns TNF-␣ from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF-␣ induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

“…43 In addition to promoting ASK1-mediated apoptosis, IRE1 activates NFkB, which can accentuate ER stressassociated tissue damage and inflammation. 10 In fact upregulation of IRE1 in the kidneys of our untreated Imai rats was accompanied by activation of NFkB. Thus, upregulation of IRE1, ASK1, phosphorylated ASK1, and phosphorylated Bcl2 in the kidneys of the untreated Imai rats points to the activation of ER stress apoptotic responses.…”

“…They include apoptosis-signalregulating kinase-1 (Ask1), nuclear factor kappa B (NFkB), IRE1, and B-cell lymphoma 2 family of protein (Bcl2) (Fig 1). [9][10][11][12] There is increasing evidence for the role of ER stress in the pathogenesis of diverse illnesses including kidney diseases. ER stress is present in glomerular cells from the animal models of membranous nephropathy and membranoproliferative glomerulonephritis.…”

Lipid signalling in disease

“…This activation results in downregulation of PPAR -dependent genes, possibly through competition for common activators, thus inhibiting adipocyte differentiation and clearing of circulating fatty acids 92 . Notably, JNK-AP-1 and IKK-NF-B are linked to components that sense and mediate ER stress and oxidative stress [93][94][95] .…”

An analysis of the sensitivity and specificity of MHC-I and MHC-II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies

“…It seems that ER stress mechanisms can activate inflammatory responses through a number of different pathways and mediators: e.g. NF-кB, JNK, reactive oxygen species, interleukin-6 and TNF-α [33,34]. Recent studies also suggest that immature muscle precursor cells are a possible source of type I interferon secretion and may be implicated in HLA class I overexpression through the activation of Toll-like Receptor 3 [35].…”