Synergistic activation of NF-κB by nontypeable
            <i>Haemophilus influenzae</i>
            and tumor necrosis factor α

Watanabe, Takahiro; Jono, Hirofumi; Han, Jiahuai; Lim, David J.; Li, Jian Dong

doi:10.1073/pnas.0400557101

Cited by 72 publications

(87 citation statements)

References 30 publications

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“…In our ER stress model, activation of p38 MAPK may be involved in enhancing nuclear NF-B DNA binding activity because inhibition of p38 MAPK decreases the DNA binding activity of NF-B with minor effects on nuclear translocation of NF-B subunits. Recently, p38 MAPK was shown to activate the NF-B transcriptional activity without affecting its nuclear translocation (53,54), which may be similar to the role of p38 MAPK in this report. The appearance of NF-B in the nucleus began 1.5 h after ER stress which is consistent with the induction of COX-2 mRNA.…”

Section: Fig 3 Activation Of Nf-b During Er Stresssupporting

confidence: 87%

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Hung

Lei³

et al. 2004

Journal of Biological Chemistry

240

215

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Expression of mutant proteins or viral infection mayinterfere with proper protein folding activity in the endoplasmic reticulum (ER). Several pathways that maintain cellular homeostasis were activated in response to these ER disturbances. Here we investigated which of these ER stress-activated pathways induce COX-2 and potentially oncogenesis. Tunicamycin and brefeldin A, two ER stress inducers, increased the expression of COX-2 in ML-1 or MCF-7 cells. Nuclear translocation of NF-B and activation of pp38 MAPK were observed during ER stress. I B␣ kinase inhibitor Bay 11-7082 or I B␣ kinase dominant negative mutant significantly inhibited the induction of COX-2. pp38 MAPK inhibitor SB203580 or eIF2␣ phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-B DNA binding activity and COX-2 induction. Expression of mutant hepatitis B virus (HBV) large surface proteins, inducers of ER stress, enhanced the expression of COX-2 in ML-1 and HuH-7 cells. Transgenic mice showed higher expression of COX-2 protein in liver and kidney tissue expressing mutant HBV large surface protein in vivo. Similarly, increased expression of COX-2 mRNA was observed in human hepatocellular carcinoma tissue expressing mutant HBV large surface proteins. In ML-1 cells expressing mutant HBV large surface protein, anchorage-independent growth was enhanced, and the enhancement was abolished by the addition of specific COX-2 inhibitors. Thus, ER stress due either to expression of viral surface proteins or drugs can stimulate the expression of COX-2 through the NF-B and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.

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Section: Fig 3 Activation Of Nf-b During Er Stresssupporting

confidence: 87%

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Hung

Lei³

et al. 2004

Journal of Biological Chemistry

240

215

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“…Recombinant mTNF-␣, hTNF-␣, and hIL-1␤ were purchased from R&D Systems. NTHi strain 12 was described previously (10,11).…”

Section: Methodsmentioning

confidence: 99%

“…Cell Culture-Human cervix epithelial cell line HeLa was maintained as described (10,11) and was used for all experiments unless otherwise indicated. All mouse embryonic fibroblast (MEF) cells were maintained as described (12)(13)(14)(15).…”

Section: Methodsmentioning

confidence: 99%

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NF-κB Is Essential for Induction of CYLD, the Negative Regulator of NF-κB

Jono

Lim

Chen

et al. 2004

Journal of Biological Chemistry

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165

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The transcription factor NF-B regulates genes involved in inflammatory and immune responses, tumorigenesis, and apoptosis. In contrast to the pleiotropic stimuli that lead to its positive regulation, the known signaling mechanisms that underlie the negative regulation of NF-B are very few. Recent studies have identified the tumor suppressor CYLD, loss of which causes a benign human syndrome called cylindromatosis, as a key negative regulator for NF-B signaling by deubiquitinating tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2, TRAF6, and NEMO (NF-B essential modulator, also known as I B kinase ␥). However, how CYLD is regulated remains unknown. The present study revealed a novel autoregulatory feedback pathway through which activation of NF-B by TNF-␣ and bacterium nontypeable Haemophilus influenzae (NTHi) induces CYLD that in turn leads to the negative regulation of NF-B signaling. In addition, TRAF2 and TRAF6 appear to be differentially involved in NF-B-dependent induction of CYLD by TNF-␣ and NTHi. These findings provide novel insights into the autoregulation of NF-B activation.The transcription factor NF-B plays critical roles in regulating inflammatory and immune responses, tumorigenesis, and protection against apoptosis (1-3). Previous studies identified an inducible feedback inhibition pathway for controlling I B␣ gene transcription and down-regulation of transient activation of NF-B (4 -6). Recent studies have identified the tumor suppressor CYLD 1 as a key negative regulator for NF-B signaling by deubiquitinating tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2, TRAF6, and NEMO (7-9). However, how CYLD is regulated is totally unknown. It is still unclear whether activation of NF-B induces CYLD transcription that in turn leads to the inhibition of NF-B especially in more delayed or persistent phase in an autoregulatory feedback manner.To determine whether CYLD is induced during inflammation, we first sought to evaluate the effects on CYLD expression of a variety of inflammation stimuli such as proinflammatory cytokines and bacteria. Having demonstrated that CYLD is indeed induced by TNF-␣, interleukin-1␤ (IL-1␤) and nontypeable Haemophilus influenzae (NTHi), an important Gramnegative bacterial pathogen for respiratory infections, we next sought to determine whether activation of NF-B is required for CYLD induction based on the fact that all of the above CYLD inducers are also potent inducers for NF-B.Here we showed that activation of NF-B is indeed required for CYLD induction by TNF-␣, IL-1␤, and NTHi and that TRAF2 and TRAF6 are differentially involved in NF-B-dependent induction of CYLD by TNF-␣ and NTHi. The present study thus revealed a novel autoregulatory feedback pathway through which activation of NF-B by TNF-␣ and NTHi induces CYLD that in turn leads to the inhibition of NF-B signaling. These findings should enhance our understanding of the negative feedback regulation of NF-B activation during inflammation. MATERIALS AND METHODSReagents-MG-132 was purchased from ...

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“…The expression plasmids TLR2 dominant negative (DN), TLR4 DN, MyD88 DN, IRAK1 DN, TRAF6 DN, I B␣ DN, ERK2 DN, IKK␣ DN, WT IKK␣, IKK␤ DN, and WT IKK␤ have been previously described (31)(32)(33)(34)(35)(36)(37). The expression plasmid ERK1 DN was provided by Dr. Cobb (University of Texas Southwestern Medical Center, Dallas, TX).…”

Section: Plasmids Transfections and Luciferase Assaysmentioning

confidence: 99%

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

Lim

Jono

et al. 2007

The Journal of Immunology

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Epithelial cells represent the first line of host innate defense against invading microbes by elaborating a range of molecules involved in pathogen clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. How mucin is induced in upper respiratory Streptococcus pneumoniae infections is unknown. In this study, we show that pneumolysin is required for up-regulation of MUC5AC mucin via TLR4-dependent activation of ERK in human epithelial cells in vitro and in mice in vivo. Interestingly, a “second wave” of ERK activation appears to be important in mediating MUC5AC induction. Moreover, IκB kinase (IKK) α and IKKβ are distinctly involved in MUC5AC induction via an ERK1-dependent, but IκBα-p65- and p100-p52-independent, mechanism, thereby revealing novel roles for IKKs in mediating up-regulation of MUC5AC mucin by S. pneumoniae.

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Synergistic activation of NF-κB by nontypeable Haemophilus influenzae and tumor necrosis factor α

Cited by 72 publications

References 30 publications

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

NF-κB Is Essential for Induction of CYLD, the Negative Regulator of NF-κB

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

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