The c-jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process

in Journal of Biological Chemistry (2012), 287(35), 29213-26

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently ... [more ▼]

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently induce various signalling pathways leading to NF- kappaB activation and autophagy, both events contributing to an efficient innate and adaptative immune response. Interestingly, loss-of-function nod2 variants were associated with a higher susceptibility for Crohn ' s disease (CD), which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-jun N-terminal kinase binding protein 1 (JNKBP1), a scaffold protein characterized by a N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following MDP activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signalling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. [less ▲]

Actin cytoskeleton differentially modulates NF-κB-mediated IL-8 expression in myelomonocytic cells

in Biochemical Pharmacology (2008), 76(10)

Many physiopathological events such as phagocytosis, pathogen invasion, cellular adhesion and chemotaxis governed by actin-based cytoskeleton are often accompanied by nuclear factor kB (NF-kB) activation ... [more ▼]

Many physiopathological events such as phagocytosis, pathogen invasion, cellular adhesion and chemotaxis governed by actin-based cytoskeleton are often accompanied by nuclear factor kB (NF-kB) activation and expression of pro-inflammatory genes. In the present study, we demonstrated that reorganization of actin cytoskeleton induced by Cytochalasin D (CytD), an actin-polymerization inhibitor, enhanced il-8 gene expression induced by TNFa and LPS in HL-60 monocyte-like cells. Both transcriptional and post-transcriptional mechanisms were involved. CytD potentiated NF-kB-mediated transcription induced by both TNFa and LPS but via different mechanisms. In the case of LPS, the perturbation of actin dynamics increased the TLR4 levels at the cell membrane and consequently enhanced the IKK complex activation and NF-kB nuclear translocation. However, the canonical pathway involving the IKK complex and leading to the NF-kB translocation into the nucleus was not affected by actin remodelling in the case of TNFa. Interestingly, actin disruption primed p65 phosphorylation induced by TNFa and LPS, on Ser276 and Ser536, respectively, which suggested actin cytoskeleton could also modulate p65 transactivating activity. [less ▲]

Bronchoalveolar lavage fluids of ventilated patients with acute lung injury activate NF-kappa B in alveolar epithelial cell line: role of reactive oxygen/nitrogen species and cytokines

in Nitric Oxide (2003), 9(1), 33-43

In human alveolar epithelial cell line, we investigated the binding activity of NF-kappaB induced by the bronchoalveolar lavage fluids (BALs) from ventilated patients with acute lung injury (ALI), in ... [more ▼]

In human alveolar epithelial cell line, we investigated the binding activity of NF-kappaB induced by the bronchoalveolar lavage fluids (BALs) from ventilated patients with acute lung injury (ALI), in correlation with the concentrations of inflammatory cytokines, RNOS, and the severity of the ALI. In BALs obtained in 67 patients (16 bronchopneumonia, 14 infected ARDS, 20 ARDS, and 17 ALI patients without bronchopneumonia and no ARDS), we measured endotoxin, IL-1beta, IL-8, and nitrated proteins (NTP), the activity of mycloperoxidase, and the capacity to activate the NF-kappaB in alveolar A549 cells by electrophoretic mobility shift and supershift assays. The neutrophil counts and mean IL-1beta, IL-8, myeloperoxidase, and NTP values were increased in bronchopneumonia and infected ARDS groups compared to ARDS and ALI without bronchopneumonia and no ARDS groups (P < 0.001). The number of neutrophils was correlated to those of IL-1beta, IL-8, myeloperoxidase, NTP, and endotoxin in all groups (P < 0.0001). NF-kappaB activity was induced in alveolar like cells by BALs in all groups, was higher in bronchopneumonia and infected ARDS groups (P < 0.02), and was correlated to IL-1beta (P = 0.0002), IL-8 (P = 0.02), NTP (P = 0.014), myeloperoxidase (P = 0.016), and neutrophil counts (P = 0.003). BALs of bronchopneumonia and infected ARDS patients had increased inflammatory mediators (compared to ARDS and ALI without bronchopneumonia and no ARDS patients) that correlated to neutrophil counts and to the NF-kappaB-binding activity. These mediators and NF-kappaB activation may induce an amplification of inflammatory phenomena. By in vitro studies, we confirmed that NO-derived species (10(-6) to 10(-5) M peroxynitrite and 10(-5) M nitrites) and myeloperoxidase (at concentration equivalent to that found in BALs) can participate in the NF-kappaB activation. (C) 2003 Elsevier Inc. All rights reserved. [less ▲]

Bronchoalveolar lavage fluids of patients with lung injury activate the transcription factor nuclear factor-kappa beta in an alveolar cell line

in Clinical Science (2002), 103(6), 577-585

In bronchoalveolar lavage (BAL) fluid from ventilated patients, cytotoxic oxidant activity is correlated with neutrophil activation. The aim of the present study was to investigate the hypothesis that BAL ... [more ▼]

In bronchoalveolar lavage (BAL) fluid from ventilated patients, cytotoxic oxidant activity is correlated with neutrophil activation. The aim of the present study was to investigate the hypothesis that BAL fluid induces activation of the transcription nuclear factor-kappaB (NF-kappaB) in human alveolar cells, in correlation with inflammatory mediators. We measured endotoxin, inflammatory cytokines [Interleukin-1beta (IL-1beta), IL-8], nitrated proteins and the activity of myeloperoxidase (MPO) in BAL fluid from ventilated patients developing bronchopneumonia (n = 19 samples) or with acute respiratory distress syndrome (ARDS) (n = 14), and from ARDS/infection-free patients (n = 11). We also exposed alveolar cells to the BAL fluid or to human MPO, H2O2 or HOCl, and tested nuclear extracts for the activation of NF-kappaB. IL-1beta, IL-8, nitrated protein, MPO and endotoxin levels were significantly higher in BAL fluid from patients with bronchopneumonia than in that from the ARDS and ARDS/infection-free groups. A correlation was observed between IL-8 and MPO values (r = 0.82). The level of NF-kappaB activity induced by the BAL fluid was correlated with levels of IL-1beta (P < 0.001), IL-8 (P < 0.005) and MPO (P < 0.002), and with the neutrophil count (P < 0.002), and was higher for BAL fluid from the bronchopneumonia group. NF-kappaB activation by MPO was also demonstrated. The activation of NF-kappaB by BAL fluid, especially that from bronchopneumonia patients, suggests that a similar phenomenon may occur in vivo, leading to potential amplification of the inflammatory reaction. [less ▲]

Regulation of interleukin-6 gene expression by pro-inflammatory cytokines in a colon cancer cell line

in Biochemical Journal (2000)

NF-kappaB: an important transcription factor in photobiology

in Journal of Photochemistry & Photobiology B : Biology (1998)

Multiple redox regulation in NF-kappaB transcription factor activation

in Biological Chemistry (1997)

Involvement of different transduction pathways in NF-kappaB activation by several inducers

in Free Radical Research (1997)

Transcription factor NF-kappaB is activated by photosensitization generating oxidative DNA damages

in Journal of Biological Chemistry (1995)

NF-kappaB transcription factor activation by hydrogen peroxide can be decreased by 2,3-dihydroxybenzoic acid and its ethylester derivative

in Archives of Biochemistry & Biophysics (1995)