NF-κB and IRF7 Pathway Activation by Epstein-Barr Virus Latent Membrane Protein 1

The principal Epstein-Barr virus (EBV) oncoprotein, Latent Membrane Protein 1 (LMP1), is expressed in most EBV-associated human malignancies. LMP1 mimics CD40 receptor signaling to provide infected cells with constitutive NF-κB, MAP kinase, IRF7, and PI3 kinase pathway stimulation. EBV-transformed B-cells are particularly dependent on constitutive NF-κB activity, and rapidly undergo apoptosis upon NF-κB blockade. Here, we review LMP1 function, with special attention to current understanding of the molecular mechanisms of LMP1-mediated NF-κB and IRF7 pathway activation. Recent advances include the elucidation of transmembrane motifs important for LMP1 trafficking and ligand-independent signaling, analysis of genome-wide LMP1 gene targets, and the identification of novel cell proteins that mediate LMP1 NF-κB and IRF7 pathway activation.     

Lipopolysaccharides Reduce Adipogenesis in 3T3-L1 Adipocytes Through Activation of NF-κB Pathway and Downregulation of AMPK Expression

Lipopolysaccharides (LPS) from the outer membrane of Gram-negative bacteria serve as endotoxin to exert potent immune responses. However, the effect of LPS on adipogenesis has not been elucidated. The present study was designed to examine the effect of LPS on adipogenesis in 3T3-L1 preadipocytes and possible mechanism(s) of action involved. Our results revealed that LPS challenge significantly suppressed adipogenesis in 3T3-L1 preadipocytes mainly through downregulated expression of the late adipogenic markers PPARγ and aP2 as well as AMP-activated protein kinase (AMPK) expression and activity. As an inflammatory factor, LPS was found to lead to an overt reduction in IκBα levels compared with the time-matched controls, consolidating its pro-inflammatory property in 3T3-L1 preadipocytes. Our data also revealed that LPS retarded adipogenesis, the effect of which was partially reversed by the selective inhibitor of IKKβ. IκBα was found to be involved in the anti-adipogenic effect of LPS. In conclusion, LPS is capable of inhibiting adipogenesis in 3T3-L1 adipocytes possibly through activation of NF-κB and inhibition of AMPK. With the activation of NF-κB pathway and inhibition of AMPK, LPS suppresses C/EBP α DNA-binding activity and the expression of late adipogenic markers PPARγ and aP2.     

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

HIV modulates plasmacytoid dendritic cell (pDC) activation via Toll-like receptor 7, inducing type I IFN and inflammatory cytokines. Simultaneously, pDCs up-regulate the expression of indoleamine 2,3 dioxygenase (IDO), which is essential for the induction of regulatory T cells (Tregs), which function to down-modulate immune activation. Here we demonstrate the crucial importance of the noncanonical NF-κB pathway in the establishment of this immunoregulatory phenotype in pDCs. In response to HIV, the noncanonical NF-κB pathway directly induces IDO and involves the recruitment of TNF receptor-associated factor-3 to the Toll-like receptor/MyD88 complex, NF-κB-inducing kinase-dependent IκB kinase-α activation, and p52/RelB nuclear translocation. We also show that pDC-induced Tregs can inhibit conventional DC (cDC) maturation partially through cytotoxic T-lymphocyte antigen (CTLA)-4 engagement. Furthermore, CTLA-4 induces IDO in cDCs in a NF-κB-inducing kinase-dependent way. These CTLA-4-conditioned cDCs can in turn induce Treg differentiation in an IDO-dependent manner. Thus, the noncanonical NF-κB pathway is integral in controlling immunoregulatory phenotypes of both pDCs and cDCs.     

Inhibition of Lipid Peroxidation, NF-κB Activation and IL-8 Production by Rebamipide in Helicobacter pylori-Stimulated Gastric Epithelial Cells

The present study aimed to investigate whether rebamipide, a novel antiulcer agent that has an oxygen radical scavenging activity, would inhibit lipid peroxidation, NF-B activation, and IL-8 production by H. pylori. Human gastric epithelial cells (AGS and KATO III), treated with rebamipide or not were incubated in the absence or the presence of H. pylori. As a result, H. pylori significantly stimulated IL-8 production, which was similar to time course stimulation of lipid peroxidation. Other cytokines (IL-1, IL-1, IL-6, TNF-) were not stimulated by H. pylori. Treatment with H. pylori resulted in the activation of two species of NF-B dimers (a p50/p65 heterodimer and a p50 homodimer). Rebamipide significantly inhibited lipid peroxidation as an indicative of oxidative damage, NF-B complex formation, and IL-8 production by H. pylori. In conclusion, rebamipide may attenuate H. pylori-induced gastric inflammation by inhibiting lipid peroxidation and oxidant-mediated activation of NF-B and thereby decreasing IL-8 production.     

Targeting HTLV-1 activation of NFκB in mouse models and ATLL patients

Of the millions of HTLV-1 infected carriers worldwide, 3-5% will develop an aggressive T-cell neoplasm that is highly refractory to conventional therapy. The virus carries the Tax oncogene which constitutively activates the NFκB pathway. This co-option of signaling through NFκB provides for the HTLV-1 infected cell an escape from cell cycle arrest and apoptosis, a steady source of growth factors, and a mechanism by which the virus can activate its own target cell. Therapies that target the NFκB pathway sensitize adult T-cell leukemia/lymphoma (ATLL) cells to apoptosis. A focus on translational interrogation of NFκB inhibitors in animal models and ATLL patients is needed to advance NFκB-targeted ATLL therapies to the bedside.     

KRAS Mutation and NF-κB Activation Indicates Tolerance of Chemotherapy and Poor Prognosis in Colorectal Cancer

Background

Evidence shows a strong relationship between KRAS mutations and the NF-κB signaling pathway. In colorectal cancer, however, the study of this subject has been very limited and results are inconsistent.

Aims

To examine the relationship between KRAS mutations and NF-κB activation and their effect on chemotherapy response and survival of colorectal cancer patients.

Materials and Methods

NF-κB activation was analyzed by immunohistochemistry in 167 primary colorectal cancer specimens in which the KRAS mutation status was confirmed. Clinical and pathologic data were extracted from the medical records and reviewed.

Results

Of 167 tumors screened, 63 (37.7?%) had NF-κB activation, 59 (35.3?%) had KRAS mutations, and 30 (18.0?%) had both NF-κB activation and KRAS mutations. The frequency of NF-κB activation in tumors with KRAS mutations was significantly higher than in tumors with wild type KRAS; 50.8 versus 30.6?%, P?=?0.012. Patients with both KRAS mutations and NF-κB activation had a lower objective response to first-line chemotherapy than patients with other tumors, 23.8 versus 49.4?% (P?=?0.035). Compared to patients with both KRAS mutations and NF-κB activation, overall survival of patients in other groups was significantly higher; median overall survival was 28.4?months (95?% CI 21.0–35.8) versus 46.3?months (95?% CI 39.4–53.2), hazard ratio 0.259 (95?% CI 0.125–0.538), P?=?0.005.

Conclusions

NF-κB activation was associated with KRAS mutation, and both KRAS mutation and NF-κB activation were indicative of high tolerance of chemotherapy and poor prognosis for colorectal cancer patients. Tumors with KRAS mutations and NF-κB activation may be a unique subtype of colorectal cancer.     

Esculetin Attenuates the Growth of Lung Cancer by Downregulating Wnt Targeted Genes and Suppressing NF-κB

Introduction

Esculetin was identified to inhibit cell proliferation and induce apoptosis or cell cycle arrest in several cancer cell lines. However, the effect of esculetin on lung cancer remains elusive.

ACEI attenuates the progression of CCl4-induced rat hepatic fibrogenesis by inhibiting TGF-β1, PDGF-BB, NF-κB and MMP-2,9

AIM: Angiotensin II has pro-fibrotic function in the liver. Blockade of the renin-angiotensin-aldosterone-system (RAAS) attenuates hepatic fibrosis. The aim of the present study was to determine the mechanism of angiotensin-converting enzyme inhibitor (ACEI) on the progression of rat hepatic fibrosis. METHODS: Forty male Wistar rats were divided into three groups. Model group (Mo): The rats were injected subcutaneously with 40% of CCl(4) 0.25 mL/100 g. Perindopril group (Pe): The rats were injected subcutaneously with 40% of CCl(4). Perindopril, equivalent to 2 mg/(kg.d), was administrated. Control group (Nc): the rats were treated with olive oil only. After 4 and 6 wk, the rats were killed. The liver sections were stained with Masson. The protein expressions of AT1R, TGF-beta1 and PDGF-BB were examined by Western blot. Nuclear factor kappaB (NF-kappaB) DNA binding activity was examined by EMSA (Electrophoretic gel mobility shift assay). Matrix metalloproteinase-2,9 (MMP-2,9) activity was assessed by zymography. Serum laminin (LN) and hyaluronic acid (HA) were measured using radioimmunoassays. RESULTS: Using Western blot, we clearly provided direct evidence for the expression of AT1R in liver. The expression was up-regulated when fibrogenesis occurred. Perindopril treatment significantly reduced mean fibrosis score, protein levels of AT1R, TGF-beta1 and PDGF-BB, serum levels of HA and LN, and the activity of MMP-2,9. NF-kappaB DNA binding activity markedly increased in model group, perindopril treatment considerably reduced NF-kappaB DNA binding activity. CONCLUSION: Perindopril attenuates CCl(4)-induced hepatic fibrogenesis of rat by inhibiting TGF-beta1, PDGF-BB, NF-kappaB and MMP-2,9.