28 results on '"Jian-Dong Li"'
Search Results
2. An update on vinpocetine: New discoveries and clinical implications
- Author
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Yi-shuai Zhang, Jian Dong Li, and Chen Yan
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0301 basic medicine ,Heart Diseases ,Dietary supplement ,Disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Vinpocetine ,medicine ,Animals ,Humans ,Dementia ,Vascular Diseases ,Vinca Alkaloids ,Stroke ,Pharmacology ,Mechanism (biology) ,business.industry ,medicine.disease ,Safety profile ,030104 developmental biology ,Nervous System Diseases ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Vinpocetine, a derivative of the alkaloid vincamine, has been clinically used in many countries for treatment of cerebrovascular disorders such as stroke and dementia for more than 30 years. Currently, vinpocetine is also available in the market as a dietary supplement to enhance cognition and memory. Due to its excellent safety profile, increasing efforts have been put into exploring the novel therapeutic effects and mechanism of actions of vinpocetine in various cell types and disease models. Recent studies have revealed a number of novel functions of vinpocetine, including anti-inflammation, antagonizing injury-induced vascular remodeling and high-fat-diet-induced atherosclerosis, as well as attenuating pathological cardiac remodeling. These novel findings may facilitate the repositioning of vinpocetine for preventing or treating relevant disorders in humans.
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- 2018
3. Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase
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Jian Dong Li, Adegboyega K. Oyelere, Kensei Komatsu, Idris O. Raji, Lindsey C. Szymczak, Shaghayegh Fathi, Emily Janeira, Milan Mrksich, James R. Kornacki, and Fatima Yadudu
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Models, Molecular ,0301 basic medicine ,Cell Survival ,Indomethacin ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Pharmacology ,Biochemistry ,Histone Deacetylases ,Article ,Cell Line ,Structure-Activity Relationship ,03 medical and health sciences ,Drug Discovery ,LNCaP ,Humans ,Structure–activity relationship ,Cyclooxygenase Inhibitors ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Cell growth ,Cell Cycle ,Organic Chemistry ,Cell cycle ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Celecoxib ,Prostaglandin-Endoperoxide Synthases ,Cell culture ,biology.protein ,Molecular Medicine ,Cyclooxygenase ,Histone deacetylase ,Drug Screening Assays, Antitumor - Abstract
We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound 11b outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development.
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- 2017
4. Panel 2- recent advance in otitis media bioinformatics
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Shyan Vijayasekaran, Arwa Kurabi, Stéphanie Val, Diego Preciado, Jian Dong Li, Kensei Komatsu, Ann Hermansson, Gustavo Nino, and Oren Ziv
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Proteomics ,Inflammasomes ,Ear, Middle ,Genomics ,Disease ,Bioinformatics ,Article ,Immunopathology ,medicine ,Humans ,Genetic Predisposition to Disease ,Innate immune system ,business.industry ,Microbiota ,Computational Biology ,General Medicine ,Immunity, Innate ,MicroRNAs ,Otitis Media ,Search terms ,Otitis ,Otorhinolaryngology ,Acute Disease ,Chronic Disease ,Pediatrics, Perinatology and Child Health ,Disease Progression ,medicine.symptom ,Analysis tools ,business ,Medical literature - Abstract
Objectives To update the medical literature on recent large-scale studies employing bioinformatics data analysis tools in otitis media (OM) disease models with a principal focus on developments in the past 5 years. Data sources Pubmed indexed peer-reviewed articles. Review methods Comprehensive review of the literature using the following search terms: ‘genomics, inflammasome, microRNA, proteomics, transcriptome, bioinformatics’ with the term ‘otitis media’, and ‘middle ear’. Included articles published in the English language from January 1, 2015–April 1, 2019. Implications for practice Large scale bioinformatics tools over the past five years lend credence to the paradigm of innate immune response playing a critical role in host defense against bacteria contributing to Otitis Media (OM) progression from acute to chronic. In total, genomic, miRNAomic, and proteomic analyses all point to the need for a tightly regulated innate immune and inflammatory response in the middle ear. Currently, there is an urgent need for developing novel therapeutic strategies to control immunopathology and tissue damage, improve hearing and enhance host defense for both acute and chronic OM based on full understanding of the basic molecular pathogenesis of OM.
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- 2020
5. Co-immunization with virus-like particle and DNA vaccines induces protection against respiratory syncytial virus infection and bronchiolitis
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Sang-Moo Kang, Min-Kyoung Cho, Jian Dong Li, Yu-Na Lee, Si-Eun Yoo, Yu-Jin Jung, Young-Tae Lee, Eun-Ju Ko, Min Chul Kim, Jong Seok Lee, Young-Man Kwon, Hye Suk Hwang, and Ji-Yun Lee
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viruses ,Respiratory Syncytial Virus Infections ,Spodoptera ,Antibodies, Viral ,Article ,Virus ,Cell Line ,DNA vaccination ,Mice ,Virology ,Eosinophilia ,Respiratory Syncytial Virus Vaccines ,Sf9 Cells ,Vaccines, DNA ,medicine ,Animals ,Bronchiolitis, Viral ,Vaccines, Virus-Like Particle ,Pulmonary pathology ,Lung ,Inflammation ,Pharmacology ,Mice, Inbred BALB C ,business.industry ,Vaccination ,virus diseases ,Th1 Cells ,Viral Load ,respiratory system ,medicine.disease ,Antibodies, Neutralizing ,Respiratory Syncytial Viruses ,Immunization ,Bronchiolitis ,Immunoglobulin G ,Immunology ,Female ,medicine.symptom ,business ,Viral Fusion Proteins - Abstract
This study demonstrates that immunization with non-replicating virus-like particle (FFG VLP) containing RSV F and G glycoproteins together with RSV F DNA induced T helper type 1 antibody responses to RSV F similar to live RSV infection. Upon RSV challenge 21 weeks after immunization, FFG VLP vaccination induced protection against RSV infection as shown by clearance of lung viral loads, and the absence of eosinophil infiltrates, and did not cause lung pathology. In contrast, formalin-inactivated RSV (FI-RSV) vaccination showed significant pulmonary eosinophilia, severe mucus production, and extensive histopathology resulting in a hallmark of pulmonary pathology. Substantial lung pathology was also observed in mice with RSV re-infections. High levels of systemic and local inflammatory cytokine-secreting cells were induced in mice with FI-RSV but not with FFG VLP immunization after RSV challenge. Therefore, the results provide evidence that recombinant RSV FFG VLP vaccine can confer long-term protection against RSV without causing lung pathology.
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- 2014
6. The prevalence, antimicrobial resistance and PFGE profiles of Laribacter hongkongensis in retail freshwater fish and edible frogs of southern China
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Ou Zhang, Jing Hu, Jian-Dong Li, Shan Liu, Jin-yan Lin, Qing Chen, Shinji Yamasaki, Jia-Li Feng, Lei Shi, and Nityananda Chowdhury
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China ,Veterinary medicine ,biology ,Fishes ,Food Contamination ,Drug resistance ,biology.organism_classification ,Antimicrobial ,Neisseriaceae ,Microbiology ,Bighead carp ,Anti-Bacterial Agents ,Electrophoresis, Gel, Pulsed-Field ,Grass carp ,Antibiotic resistance ,Seafood ,Drug Resistance, Bacterial ,Laribacter hongkongensis ,Freshwater fish ,Pulsed-field gel electrophoresis ,Animals ,Anura ,Phylogeny ,Food Science - Abstract
Laribacter hongkongensis is a novel emerging pathogen associated with human gastroenteritis. We aimed to investigate the prevalence, antimicrobial resistance and genotypic relationship of 199 L. hongkongensis isolates from 690 intestinal samples of fish and frogs. These samples were collected from retail markets in the city of Guangzhou in southern China from October 2008 to September 2009. L. hongkongensis was detected in from 80 (16.3%) out of 490 freshwater fish, and this number included 76 (32.3%) out of 235 grass carp and 4 (14.8%) out of 27 bighead carp. A higher isolation rate of 59.5% (119 out of 200) was observed in edible frogs. The isolation rate was highest in the spring in comparison with other seasons. Notably, 63.8% of the isolates were resistant to at least one class of antimicrobial agents. Analysis by pulsed-field gel electrophoresis (PFGE) revealed that the isolates could be grouped into three clusters. Isolates from fish intestines were grouped into two clusters: cluster I and II. Isolates of frog-origin and several fish-origin isolates were grouped into cluster III. Two patient-derived strains could be classed into cluster III. Extensive genetic heterogeneity among the isolates was observed. The results indicate that L. hongkongensis isolates exhibits host tropism, extensive resistance to widely used antimicrobials and diverse biological evolution in an aquatic environment. The frog is more likely than the freshwater fish to be the potential source for human infection with L. hongkongensis.
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- 2012
7. Practical robust uniform channel decomposition scheme for CSI mismatch in limited feedback MIMO systems
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Jian-dong Li, Rui Chen, and Wei Liu
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Lossless compression ,Matching (graph theory) ,Computer Networks and Communications ,Computer science ,Transmitter ,Vector quantization ,Context (language use) ,Data_CODINGANDINFORMATIONTHEORY ,Channel state information ,Control theory ,Signal Processing ,Bit error rate ,Computer Science::Information Theory ,Information Systems ,Communication channel - Abstract
Uniform channel decomposition (UCD) has been proven to be optimal in bit error rate (BER) performance and strictly capacity lossless when perfect channel state information (CSI) is assumed to be available at both the transmitter and receiver side. In practice, CSI can be obtained by channel estimation at receiver and conveyed to transmitter via a limited-rate feedback channel. In such case, the implementation of traditional UCD by treating the imperfect CSI as perfect CSI cause significant performance degradation due to inevitable channel estimation error and vector quantization error. To overcome this problem, a practical robust UCD scheme was proposed in this paper, which includes two steps, firstly, a matching architecture was proposed to eliminate the mismatch between CSI at receiver (CSIR) and CSI at transmitter (CSIT), secondly, an MMSE based robust UCD scheme considering channel estimation error and vector quantization error as an integral part of the design was derived. Simulation results show that the proposed practical robust UCD scheme is capable of improving the BER performance greatly in the context of channel estimation error and vector quantization error compared with the traditional UCD scheme.
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- 2010
8. Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK
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Akira Imasato, Hirofumi Jono, Jae Hyang Lim, Chen Yan, Jian Dong Li, Haidong Xu, Hirofumi Kai, and Kensei Komatsu
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Haemophilus Infections ,p38 mitogen-activated protein kinases ,Biophysics ,Mucin 5AC ,Biology ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Dexamethasone ,Dephosphorylation ,Pulmonary Disease, Chronic Obstructive ,Glucocorticoid receptor ,Immune system ,Cell Line, Tumor ,otorhinolaryngologic diseases ,medicine ,Humans ,Phosphorylation ,Glucocorticoids ,Molecular Biology ,Mucin ,Dual Specificity Phosphatase 1 ,Cell Biology ,Haemophilus influenzae ,Otitis Media ,Immunology ,MAPK phosphatase ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Glucocorticoids are highly effective in the control of many inflammatory and immune diseases. Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, the molecular basis for the inhibitory effect of glucocorticoids on mucin overproduction, a hallmark of chronic respiratory diseases, still remains unclear. Here we show that glucocorticoids markedly inhibit up-regulation of MUC5AC induced by NTHi, a major human bacterial pathogen causing chronic obstructive pulmonary disease and otitis media. Inhibition of NTHi-induced MUC5AC expression by dexamethasone occurs at the level of p38 MAPK via glucocorticoid receptor. Moreover, glucocorticoids up-regulate MKP-1 expression, which in turn leads to p38 dephosphorylation and the subsequent inhibition of NTHi-induced MUC5AC expression. These studies provide new insight into the molecular mechanism underlying glucocorticoid therapy and may lead to novel therapeutic intervention for inhibiting mucin overproduction in patients with NTHi infections.
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- 2008
9. Tumor Suppressor Cylindromatosis Acts as a Negative Regulator for Streptococcus pneumoniae-induced NFAT Signaling
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Chen Yan, Haidong Xu, Tomoaki Koga, Hajime Ishinaga, Jae Hyang Lim, Unhwan Ha, Hirofumi Kai, Jian Dong Li, Hirofumi Jono, Saori Morino, and Xiangbin Xu
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MAP Kinase Kinase 3 ,Biology ,Mitogen-activated protein kinase kinase ,medicine.disease_cause ,Models, Biological ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Cell Line ,Mice ,Bacterial Proteins ,Streptococcus pneumoniae ,medicine ,Animals ,Humans ,Molecular Biology ,Transcription factor ,Pneumolysin ,NFATC Transcription Factors ,MAP kinase kinase kinase ,Calcineurin ,Tumor Suppressor Proteins ,Mechanisms of Signal Transduction ,Ubiquitination ,NFAT ,Cell Biology ,MAP Kinase Kinase Kinases ,Toll-Like Receptor 2 ,Deubiquitinating Enzyme CYLD ,Cell biology ,Toll-Like Receptor 4 ,Cysteine Endopeptidases ,Streptolysins ,Cancer research ,Inflammation Mediators ,Signal transduction ,Signal Transduction - Abstract
Gram-positive bacterium Streptococcus pneumoniae is an important human pathogen that colonizes the upper respiratory tract and is also the major cause of morbidity and mortality worldwide. S. pneumoniae causes invasive diseases such as pneumonia, meningitis, and otitis media. Despite the importance of pneumococcal diseases, little is known about the molecular mechanisms by which S. pneumoniae-induced inflammation is regulated, especially the negative regulatory mechanisms. Here we show that S. pneumoniae activates nuclear factor of activated T cells (NFAT) signaling pathway and the subsequent up-regulation of inflammatory mediators via a key pneumococcal virulence factor, pneumolysin. We also demonstrate that S. pneumoniae activates NFAT transcription factor independently of Toll-like receptors 2 and 4. Moreover, S. pneumoniae induces NFAT activation via both Ca2+-calcineurin and transforming growth factor-β-activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase (MKK) 3/6-p38α/β-dependent signaling pathways. Interestingly, we found for the first time that tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for S. pneumoniae-induced NFAT signaling pathway via a deubiquitination-dependent mechanism. Finally, we showed that CYLD interacts with and deubiquitinates TAK1 to negatively regulate the activation of the downstream MKK3/6-p38α/β pathway. Our studies thus bring new insights into the molecular pathogenesis of S. pneumoniae infections through the NFAT-dependent mechanism and further identify CYLD as a negative regulator for NFAT signaling, thereby opening up new therapeutic targets for these diseases.
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- 2008
10. Reactive oxygen species regulate Pseudomonas aeruginosa lipopolysaccharide-induced MUC5AC mucin expression via PKC-NADPH oxidase-ROS-TGF-α signaling pathways in human airway epithelial cells
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Wen Li, Hirofumi Jono, Jian Dong Li, Shuangmei Zhang, Fugui Yan, Qingmei Li, and Huahao Shen
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Lipopolysaccharides ,Biophysics ,Respiratory Mucosa ,Mucin 5AC ,medicine.disease_cause ,Biochemistry ,Cystic fibrosis ,Cell Line ,Microbiology ,medicine ,Humans ,Molecular Biology ,Protein Kinase C ,Protein kinase C ,chemistry.chemical_classification ,Oxidase test ,Reactive oxygen species ,NADPH oxidase ,Dose-Response Relationship, Drug ,biology ,Pseudomonas aeruginosa ,Mucin ,Mucins ,NADPH Oxidases ,Cell Biology ,Transforming Growth Factor alpha ,medicine.disease ,chemistry ,biology.protein ,Signal transduction ,Reactive Oxygen Species ,Signal Transduction - Abstract
Mucin overproduction is a hallmark of chronic inflammatory airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Excessive production of mucin leads to airway mucus obstruction and contributes to morbidity and mortality in these diseases. The molecular mechanisms underlying mucin overproduction, however, still remain largely unknown. Here, we report that the bacterium P. aeruginosa, an important human respiratory pathogen causing cystic fibrosis, utilizes reactive oxygen species (ROS) to up-regulate MUC5AC mucin expression. Pseudomonas aeruginosa lipopolysaccharide (PA-LPS) induces production of ROS through protein kinase C (PKC)-NADPH oxidase signaling pathway in human epithelial cells. Subsequently, ROS generation by PA-LPS releases transforming growth factor-alpha (TGF-alpha), which in turn, leads to up-regulate MUC5AC expression. These findings may bring new insights into the molecular pathogenesis of P. aeruginosa infections and lead to novel therapeutic intervention for inhibiting mucin overproduction in patients with P. aeruginosa infections.
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- 2008
11. Synergistic activation of NF-κB by nontypeable H. influenzae and S. pneumoniae is mediated by CK2, IKKβ-IκBα, and p38 MAPK
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Haidong Xu, Soo Mi Kweon, Lin Feng Chen, Hajime Ishinaga, Hirofumi Jono, Beinan Wang, Jae Hyang Lim, Jian Dong Li, Davida D. Rixter, and Tomoaki Koga
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p38 mitogen-activated protein kinases ,Biophysics ,Inflammation ,NF-κB ,Cell Biology ,Biology ,medicine.disease_cause ,Biochemistry ,Microbiology ,chemistry.chemical_compound ,IκBα ,chemistry ,In vivo ,Streptococcus pneumoniae ,medicine ,medicine.symptom ,Casein kinase 2 ,Signal transduction ,Molecular Biology - Abstract
In review of the past studies on NF-kappaB regulation, most of them have focused on investigating how NF-kappaB is activated by a single inducer at a time. Given the fact that, in mixed bacterial infections in vivo, multiple inflammation inducers, including both nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae, are present simultaneously, a key issue that has yet to be addressed is whether NTHi and S. pneumoniae simultaneously activate NF-kappaB and the subsequent inflammatory response in a synergistic manner. Here, we show that NTHi and S. pneumoniae synergistically induce NF-kappaB-dependent inflammatory response via activation of multiple signaling pathways in vitro and in vivo. The classical IKKbeta-IkappaBalpha and p38 MAPK pathways are involved in synergistic activation of NF-kappaB via two distinct mechanisms, p65 nuclear translocation-dependent and -independent mechanisms. Moreover, casein kinase 2 (CK2) is involved in synergistic induction of NF-kappaB via a mechanism dependent on phosphorylation of p65 at both Ser536 and Ser276 sites. These studies bring new insights into the molecular mechanisms underlying the NF-kappaB-dependent inflammatory response in polymicrobial infections and may lead to development of novel therapeutic strategies for modulating inflammation in mixed infections for patients with otitis media and chronic obstructive pulmonary diseases.
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- 2006
12. The Transforming Growth Factor-β-Smad3/4 Signaling Pathway Acts as a Positive Regulator for TLR2 Induction by Bacteria via a Dual Mechanism Involving Functional Cooperation with NF-κB and MAPK Phosphatase 1-dependent Negative Cross-talk with p38 MAPK
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Hirofumi Kai, Tomoaki Koga, Jian Dong Li, He Gu, Jae Hyang Lim, Fumi Mikami, Unhwan Ha, Hajime Ishinaga, and Hirofumi Jono
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Regulation of gene expression ,biology ,Regulator ,NF-κB ,Cell Biology ,Transforming growth factor beta ,Biochemistry ,Cell biology ,chemistry.chemical_compound ,chemistry ,MAPK phosphatase ,MAP kinase phosphatase ,biology.protein ,Signal transduction ,Molecular Biology ,Transforming growth factor - Abstract
The transforming growth factor beta (TGF-beta) pathway represents an important signaling pathway involved in the regulation of diverse biological processes, including cell proliferation, differentiation, and apoptosis. Despite the known role of TGF-betaR-mediated signaling in suppressing immune response, its role in regulating human Toll-like receptors (TLRs), key host defense receptors that recognize invading bacterial pathogens, however, remains unknown. Here, we show for the first time that TGF-betaR-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacterium nontypeable Hemophilus influenzae (NTHi) in vitro and in vivo. The positive regulation of TLR2 induction by TGF-betaR is mediated via a dual mechanism involving distinct signaling pathways. One mechanism involves functional cooperation between the TGF-betaR-Smad3/4 pathway and NF-kappaB pathway. Another involves MAP kinase phosphatase 1 (MKP-1)-dependent inhibition of p38 MAPK, a known negative regulator for TLR2 induction. Moreover, we showed that TbetaR-mediated signaling is probably activated by NTHi-derived TGF-beta mimicry molecule via an autocrine-independent mechanism. Thus, our study provides new insights into the role of TGF-beta signaling in positively regulating host defense response by tightly controlling the expression level of TLR2 during bacterial infections and may lead to new therapeutic strategies for modulating host defense and inflammatory response.
- Published
- 2006
13. The Tumor Suppressor Cylindromatosis (CYLD) Acts as a Negative Regulator for Toll-like Receptor 2 Signaling via Negative Cross-talk with TRAF6 and TRAF7
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Hiroki Yoshida, Jian Dong Li, Hirofumi Kai, and Hirofumi Jono
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Transcription, Genetic ,MAP Kinase Kinase 3 ,Gene Expression ,Apoptosis ,Ligands ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Deubiquitinating Enzyme CYLD ,law.invention ,NF-KappaB Inhibitor alpha ,law ,Homeostasis ,Genes, Tumor Suppressor ,RNA, Small Interfering ,Feedback, Physiological ,Toll-like receptor ,NF-kappa B ,Acquired immune system ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,I-kappa B Kinase ,Cell biology ,I-kappa B Proteins ,medicine.symptom ,Oligopeptides ,Signal Transduction ,Inflammation ,Peptidoglycan ,Biology ,Transfection ,Cell Line ,Lipopeptides ,Immune system ,medicine ,Humans ,Molecular Biology ,TNF Receptor-Associated Factor 6 ,Innate immune system ,Tumor Necrosis Factor-alpha ,Ubiquitin ,Tumor Suppressor Proteins ,Interleukin-8 ,Receptor Cross-Talk ,Cell Biology ,Toll-Like Receptor 2 ,TLR2 ,Suppressor ,HeLa Cells ,Interleukin-1 - Abstract
Toll-like receptor 2 (TLR2) plays an important role in host defense against bacterial pathogens. Activation of TLR2 signaling not only induces the activation of innate immunity and instructs the development of the acquired immunity but also leads to the detrimental inflammatory responses in inflammatory and infectious diseases. To avoid detrimental inflammatory responses, TLR2 signaling must be tightly regulated. In contrast to the relative known positive regulation of TLR2 signaling, its negative regulation, however, is largely unknown. In addition the distal signaling components that link TLR2 to its downstream signaling pathways have yet to be further defined. In the present study we have provided direct evidence for the negative regulation of TLR2 signaling by the tumor suppressor cylindromatosis (CYLD). We showed that activation of TLR2 signaling by TLR2 ligands including peptidoglycan (PGN), MALP-2, and Pam3CSK4 induces activation of IKKs-IkappaBalpha and MKK3/6-p38 pathways not only by TRAF6 but also by TRAF7, a recently identified TRAF family member. The activation of both pathways leads to the transcription of TNF-alpha, IL-1beta, and IL-8 as well as CYLD. CYLD in turn leads to the inhibition of TRAF6 and TRAF7 likely via a deubiquitination-dependent mechanism. The present studies thus unveil a novel autoregulatory feedback mechanism that negatively controls TLR2-IKKs-IkappaBalpha/MKK3/6-p38-NF-kappaB-dependent induction of immune and inflammatory responses via negatively cross-talking with both TRAF6 and TRAF7. These findings provide novel insights into autoregulation and negative regulation of TLR signaling.
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- 2005
14. Epidermal Growth Factor Receptor Acts as a Negative Regulator for Bacterium Nontypeable Haemophilus influenzae-induced Toll-like Receptor 2 Expression via an Src-dependent p38 Mitogen-activated Protein Kinase Signaling Pathway
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Fumi Mikami, Hirofumi Kai, Jian Dong Li, Hirofumi Jono, He Gu, and Ali Andalibi
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Time Factors ,MAP Kinase Signaling System ,MAP Kinase Kinase 3 ,Cellular differentiation ,Blotting, Western ,Down-Regulation ,Enzyme-Linked Immunosorbent Assay ,MAP Kinase Kinase 6 ,Transfection ,Models, Biological ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Mice ,Cell Movement ,Cell Adhesion ,Animals ,Humans ,Immunoprecipitation ,ERBB3 ,RNA, Messenger ,Epidermal growth factor receptor ,Phosphorylation ,Receptor ,Molecular Biology ,Mice, Inbred BALB C ,Toll-like receptor ,Epidermal Growth Factor ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Differentiation ,Epithelial Cells ,Cell Biology ,Haemophilus influenzae ,Recombinant Proteins ,Toll-Like Receptor 2 ,Cell biology ,ErbB Receptors ,TLR2 ,src-Family Kinases ,Gene Expression Regulation ,Immune System ,biology.protein ,RNA Interference ,Signal transduction ,HeLa Cells ,Plasmids ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Epidermal growth factor receptor (EGFR) has been shown to play important roles in regulating diverse biological processes, including cell growth, differentiation, apoptosis, adhesion, and migration. Its role in regulating human Toll-like receptors (TLRs), key host defense receptors that recognize invading bacterial pathogens, however, remains unknown. Here we show for the first time that EGFR acts as a negative regulator for TLR2 induction by the bacterium nontypeable Haemophilus influenzae (NTHi) in vitro and in vivo. The negative regulation of TLR2 induction by EGFR is mediated via an Src-MKK3/6-p38 alpha/beta MAP kinase-dependent mechanism. Moreover, direct activation of EGFR signaling by the bacterium NTHi-derived EGF-like factor appears to be responsible for triggering the downstream Src-MKK3/6-p38 MAPK signaling, which in turn leads to the negative regulation of TLR2 induction. Finally, exogenous EGF increases NTHi invasion of host epithelial cells, thereby demonstrating the biological significance of TLR2 regulation by EGFR signaling. The evidence we provided in the present study may suggest a novel strategy utilized by bacteria to attenuate host defensive and immune response by negatively regulating the expression of host defense receptor TLR2. These studies may bring new insight for fully understanding the important role of EGFR signaling in regulating host defense and immune response by tightly controlling TLR2 induction during bacterial infections.
- Published
- 2005
15. Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2–TAK1-dependent p38 MAPK-AP1 and IKKβ-IκBα-NF-κB signaling pathways
- Author
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Jae Hyang Lim, Ran Chen, Hirofumi Jono, Jian Dong Li, Young S. Kim, Timothy F. Murphy, Xin Xing Gu, and Carol Basbaum
- Subjects
Transcription, Genetic ,Mucin 5AC ,medicine.disease_cause ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Haemophilus influenzae ,Mice ,chemistry.chemical_compound ,NF-KappaB Inhibitor alpha ,Luciferases ,Cells, Cultured ,Mice, Inbred BALB C ,Membrane Glycoproteins ,Reverse Transcriptase Polymerase Chain Reaction ,Toll-Like Receptors ,NF-kappa B ,MAP Kinase Kinase Kinases ,I-kappa B Kinase ,Up-Regulation ,AP-1 transcription factor ,I-kappa B Proteins ,Signal transduction ,Bacterial outer membrane ,Plasmids ,Signal Transduction ,Lipoproteins ,Blotting, Western ,Biophysics ,Receptors, Cell Surface ,Protein Serine-Threonine Kinases ,Biology ,Transfection ,Models, Biological ,Microbiology ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Molecular Biology ,DNA Primers ,Cell Membrane ,Mucin ,Mucins ,NF-κB ,Cell Biology ,Toll-Like Receptor 2 ,Enzyme Activation ,Transcription Factor AP-1 ,TLR2 ,IκBα ,chemistry - Abstract
Mucin overproduction is a hallmark of nontypeable Haemophilus influenzae (NTHi) infections. The molecular mechanisms underlying up-regulation of mucin in NTHi infections especially during the initial phase remain unknown. Here we show that P6, a 16-kDa outer membrane lipoprotein well conserved in NTHi, up-regulates MUC5AC mucin gene transcription in vitro and in vivo. Moreover, P6 induces MUC5AC transcription via TLR2-MyD88-IRAK1-TRAF6-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. This study may bring new insights into the molecular pathogenesis of NTHi-induced infections and lead to novel therapeutic intervention for inhibiting mucin overproduction in patients with NTHi infections.
- Published
- 2004
16. NF-κB Is Essential for Induction of CYLD, the Negative Regulator of NF-κB
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Eirini Trompouki, George Mosialos, Hirofumi Jono, Jian Dong Li, Zhixing K. Pan, Lin Feng Chen, Haidong Xu, and Jae Hyang Lim
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Regulation of gene expression ,TRAF2 ,I-Kappa-B Kinase ,NF-κB ,Cell Biology ,Biology ,medicine.disease_cause ,Biochemistry ,Deubiquitinating Enzyme CYLD ,Cell biology ,chemistry.chemical_compound ,chemistry ,Immunology ,medicine ,Tumor necrosis factor alpha ,Carcinogenesis ,Molecular Biology ,Transcription factor - Abstract
The transcription factor NF-kappaB 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-kappaB 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-kappaB signaling by deubiquitinating tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2, TRAF6, and NEMO (NF-kappaB essential modulator, also known as IkappaB kinase gamma). However, how CYLD is regulated remains unknown. The present study revealed a novel autoregulatory feedback pathway through which activation of NF-kappaB by TNF-alpha and bacterium nontypeable Haemophilus influenzae (NTHi) induces CYLD that in turn leads to the negative regulation of NF-kappaB signaling. In addition, TRAF2 and TRAF6 appear to be differentially involved in NF-kappaB-dependent induction of CYLD by TNF-alpha and NTHi. These findings provide novel insights into the autoregulation of NF-kappaB activation.
- Published
- 2004
17. Inhibition of p38 MAPK by Glucocorticoids via Induction of MAPK Phosphatase-1 Enhances Nontypeable Haemophilus influenzae-induced Expression of Toll-like Receptor 2
- Author
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Andrew C.B. Cato, Shizuo Akira, Christèle Desbois-Mouthon, Jian Dong Li, Jiahuai Han, Hirofumi Kai, and Akira Imasato
- Subjects
MAPK/ERK pathway ,Time Factors ,Cell Cycle Proteins ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Dexamethasone ,Protein Phosphatase 1 ,Phosphoprotein Phosphatases ,Drosophila Proteins ,Phosphorylation ,Receptor ,Cells, Cultured ,Protein Synthesis Inhibitors ,Toll-like receptor ,Membrane Glycoproteins ,Reverse Transcriptase Polymerase Chain Reaction ,Toll-Like Receptors ,Up-Regulation ,Cell biology ,Tumor necrosis factor alpha ,Mitogen-Activated Protein Kinases ,Signal transduction ,Plasmids ,Protein Binding ,Signal Transduction ,MAP Kinase Signaling System ,Blotting, Western ,Bronchi ,Receptors, Cell Surface ,Biology ,Transfection ,Models, Biological ,Immediate-Early Proteins ,Immune system ,Humans ,Glucocorticoids ,Molecular Biology ,Tumor Necrosis Factor-alpha ,Interleukin-8 ,Dual Specificity Phosphatase 1 ,Cell Biology ,Haemophilus influenzae ,Toll-Like Receptor 2 ,TLR2 ,Protein Biosynthesis ,Immunology ,MAPK phosphatase ,Protein Tyrosine Phosphatases ,HeLa Cells ,Interleukin-1 - Abstract
Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, their role in enhancing host immune and defense response against invading bacteria is poorly understood. We have demonstrated recently that glucocorticoids synergistically enhance nontypeable Haemophilus influenzae (NTHi)-induced expression of Toll-like receptor 2 (TLR2), an important TLR family member that has been shown to play a critical role in host immune and defense response. However, the molecular mechanisms underlying the glucocorticoid-mediated enhancement of TLR2 induction still remain unknown. Here we show that glucocorticoids synergistically enhance NTHi-induced TLR2 expression via specific up-regulation of the MAPK phosphatase-1 (MKP-1) that, in turn, leads to dephosphorylation and inactivation of p38 MAPK, the negative regulator for TLR2 expression. Moreover, increased expression of TLR2 in epithelial cells greatly enhances the NTHi-induced expression of several key cytokines, including tumor necrosis factor-alpha and interleukins 1beta and 8, thereby contributing significantly to host immune and defense response. These studies may bring new insights into the novel role of glucocorticoids in orchestrating and optimizing host immune and defense responses during bacterial infections and enhance our understanding of the signaling mechanisms underlying the glucocorticoid-mediated attenuation of MAPKs.
- Published
- 2002
18. Transforming Growth Factor-β-Smad Signaling Pathway Cooperates with NF-κB to Mediate NontypeableHaemophilus influenzae-induced MUC2 Mucin Transcription
- Author
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Hirofumi Jono, Shoji Yamaoka, David J. Lim, Young S. Kim, Hirofumi Kai, Haidong Xu, Xin-Hua Feng, James R. Gum, Jian Dong Li, and Tsuyoshi Shuto
- Subjects
Receptors, Steroid ,Transcription, Genetic ,Smad Proteins ,Mucin 2 ,SMAD ,Biochemistry ,chemistry.chemical_compound ,NF-KappaB Inhibitor alpha ,Genes, Reporter ,Transforming Growth Factor beta ,Drosophila Proteins ,Receptors, Immunologic ,Promoter Regions, Genetic ,Membrane Glycoproteins ,Receptors, Thyroid Hormone ,biology ,Toll-Like Receptors ,NF-kappa B ,I-kappa B Kinase ,Cell biology ,DNA-Binding Proteins ,Autocrine Communication ,I-kappa B Proteins ,Signal transduction ,Signal Transduction ,Receptors, Cell Surface ,Protein Serine-Threonine Kinases ,Models, Biological ,Cell Line ,Microbiology ,Humans ,Serotyping ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Mucin-2 ,Mucins ,NF-κB ,Cell Biology ,Transforming growth factor beta ,NFKB1 ,Antigens, Differentiation ,Haemophilus influenzae ,Toll-Like Receptor 2 ,Gene Expression Regulation ,chemistry ,Genes, Bacterial ,Myeloid Differentiation Factor 88 ,Trans-Activators ,biology.protein ,Transforming growth factor - Abstract
Transforming growth factor-beta (TGF-beta) and related factors are multifunctional cytokines that regulate diverse cellular processes, including proliferation, differentiation, apoptosis, and immune response. The involvement of TGF-beta receptor-mediated signaling in bacteria-induced up-regulation of mucin, a primary innate defensive response for mammalian airways, however, still remains unknown. Here, we report that the bacterium nontypeable Haemophilus influenzae (NTHi), an important human respiratory pathogen, utilizes the TGF-beta-Smad signaling pathway together with the TLR2-MyD88-TAK1-NIK-IKKbeta/gamma-IkappaBalpha pathway to mediate NF-kappaB-dependent MUC2 mucin transcription. The NTHi-induced TGF-beta receptor Type II phosphorylation occurred at as early as 5 min. Pretreatment of NTHi with TGF-beta neutralization antibody reduced up-regulation of MUC2 transcription. Moreover, functional cooperation of NF-kappaB p65/p50 with Smad3/4 appears to positively mediate NF-kappaB-dependent MUC2 transcription. These data are the first to demonstrate the involvement of TGF-beta receptor-mediated signaling in bacteria-induced up-regulation of mucin transcription, bring insights into the novel role of TGF-beta signaling in bacterial pathogenesis, and may lead to new therapeutic intervention of NTHi infections.
- Published
- 2002
19. Phorbol 12-Myristate 13-Acetate Up-regulates the Transcription of MUC2Intestinal Mucin via Ras, ERK, and NF-κB
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Carol Basbaum, Dae-Ho Ahn, Jian Dong Li, Sang-Young Han, Young S. Kim, David E. Szymkowski, Nancy Q. Fan, Hae-Wan Lee, Suzanne C. Crawley, Bong Hwa Lee, James R. Gum, and Marvin H. Sleisenger
- Subjects
Transcriptional Activation ,Time Factors ,Transcription, Genetic ,Mitogen-activated protein kinase kinase ,Models, Biological ,Biochemistry ,Cell Line ,MAP2K7 ,chemistry.chemical_compound ,Tumor Cells, Cultured ,Humans ,c-Raf ,Enzyme Inhibitors ,Luciferases ,Promoter Regions, Genetic ,Molecular Biology ,Protein Kinase C ,Genes, Dominant ,Cell Nucleus ,Mucin-2 ,Binding Sites ,Dose-Response Relationship, Drug ,biology ,MAP kinase kinase kinase ,Cyclin-dependent kinase 4 ,Cyclin-dependent kinase 2 ,Mucins ,NF-kappa B ,Cell Biology ,KT5720 ,Cyclic AMP-Dependent Protein Kinases ,Molecular biology ,digestive system diseases ,Up-Regulation ,chemistry ,Colonic Neoplasms ,Mutation ,ras Proteins ,biology.protein ,RNA ,Tetradecanoylphorbol Acetate ,Cyclin-dependent kinase 9 ,Mitogen-Activated Protein Kinases ,Signal Transduction - Abstract
MUC2 is a secretory mucin normally expressed by goblet cells of the intestinal epithelium. It is overexpressed in mucinous type colorectal cancers but down-regulated in colorectal adenocarcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment of colon cancer cell lines increases MUC2 expression, so we have undertaken a detailed analysis of the effects of PMA on the promoter activity of the 5'-flanking region of the MUC2 gene using stably and transiently transfected promoter reporter vectors. Protein kinase C inhibitors (bisindolylmaleimide, calphostin C) and inhibitors of mitogen-activated protein/extracellular signal regulated kinase kinase (MEK) (PD98059 and U0126) suppressed up-regulation of MUC2. Src tyrosine kinase inhibitor PP2, a protein kinase A inhibitor (KT5720), and a p38 inhibitor (SB 203580) did not affect transcription. Western blotting and reverse transcription-PCR analysis confirmed these results. In addition, co-transfections with mutants of Ras, Raf, and MEK showed that the induction of MUC2 promoter activity by PMA required these three signaling proteins. Our results demonstrate that PMA activates protein kinase C, stimulating MAP kinase through a Ras- and Raf-dependent mechanism. An important role for nuclear factor kappaB (NF-kappaB) was also demonstrated using the inhibitor caffeic acid phenethyl ester and electrophoretic mobility shift assays. Such identification of pathways involved in MUC2 up-regulation by PMA in the HM3 colon cancer cell line may serve as a model for the effects of cytokines and growth factors, which regulate MUC2 expression during the progression of colorectal cancer.
- Published
- 2002
20. Activation of a Src-dependent Raf–MEK1/2–ERK signaling pathway is required for IL-1α-induced upregulation of β-defensin 2 in human middle ear epithelial cells
- Author
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Sung Ho Kang, Mitsuyoshi Nagura, Young Myoung Chun, David J. Lim, Jian Dong Li, Ali Andalibi, Fred H. Linthicum, Tomas Ganz, Sung Kyun Moon, and Haa Yung Lee
- Subjects
Lipopolysaccharides ,beta-Defensins ,Lipopolysaccharide ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,Ear, Middle ,Protein Serine-Threonine Kinases ,Middle ear epithelial cell ,Models, Biological ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Animals ,Humans ,RNA, Messenger ,Src-dependent ,Molecular Biology ,Cells, Cultured ,030304 developmental biology ,Mitogen-Activated Protein Kinase Kinases ,0303 health sciences ,Mucous Membrane ,Innate immune system ,biology ,Tumor Necrosis Factor-alpha ,Lactoferrin ,Interleukin ,Epithelial Cells ,Cell Biology ,Protein-Tyrosine Kinases ,Immunohistochemistry ,Rats ,Up-Regulation ,3. Good health ,Cell biology ,Proto-Oncogene Proteins c-raf ,src-Family Kinases ,β-defensin 2 ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Tumor necrosis factor alpha ,Mitogen-Activated Protein Kinases ,Signal transduction ,Interleukin-1 ,Signal Transduction - Abstract
beta-defensin 2 is produced by a variety of epithelial cell types in the body and exhibits potent antimicrobial activity against a variety of pathogens, including the bacteria that are most commonly associated with otitis media (OM). The human beta-defensin 2 (hBD-2) gene is an NF-kappa B regulated gene and a variety of proinflammatory stimuli can induce its expression. Although the presence of molecules of innate immunity such as lysozyme and lactoferrin has been demonstrated in the middle ear, to date there have been no reports on the expression of beta-defensin 2. In the present study, we demonstrate that beta-defensin 2 is expressed in the middle ear mucosa of humans and rats. We also show that it is expressed in a human middle ear epithelial cell line and that its expression is induced by proinflammatory stimuli such as interleukin 1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF-alpha), and lipopolysaccharide (LPS). Moreover, we demonstrate that the transcriptional activation of hBD-2 gene by IL-1 alpha is mediated through an Src-dependent Raf-MEK1/2-ERK signaling pathway.
- Published
- 2002
21. Novel Cytoplasmic Proteins of Nontypeable Haemophilus influenzae Up-regulate Human MUC5AC Mucin Transcription via a Positive p38 Mitogen-activated Protein Kinase Pathway and a Negative Phosphoinositide 3-Kinase-Akt Pathway
- Author
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Jiahuai Han, Jian Dong Li, Young S. Kim, Beinan Wang, David J. Lim, and Carol Basbaum
- Subjects
Adult ,Haemophilus Infections ,Transcription, Genetic ,MAP Kinase Signaling System ,Morpholines ,p38 mitogen-activated protein kinases ,Mucin 5AC ,Protein Serine-Threonine Kinases ,Biology ,Cell Fractionation ,medicine.disease_cause ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Cell Line ,Microbiology ,Haemophilus influenzae ,Wortmannin ,Pathogenesis ,Phosphatidylinositol 3-Kinases ,Pulmonary Disease, Chronic Obstructive ,Viral Proteins ,chemistry.chemical_compound ,Genes, Reporter ,Proto-Oncogene Proteins ,otorhinolaryngologic diseases ,medicine ,Humans ,Enzyme Inhibitors ,Child ,Protein kinase A ,Molecular Biology ,Phosphoinositide-3 Kinase Inhibitors ,Otitis Media with Effusion ,Mucin ,Mucins ,Cell Biology ,NFKB1 ,Up-Regulation ,Androstadienes ,chemistry ,Chromones ,Immunology ,Mitogen-Activated Protein Kinases ,Signal transduction ,Proto-Oncogene Proteins c-akt - Abstract
Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen that causes chronic otitis media with effusion (COME) in children and exacerbation of chronic obstructive pulmonary disease (COPD) in adults. Mucin overproduction, a hallmark of both diseases, has been shown to directly cause conductive hearing loss in COME and airway obstruction in COPD. The molecular mechanisms underlying mucin overproduction in NTHi infections still remain unclear. Here, we show that NTHi strongly up-regulates MUC5AC mucin transcription only after bacterial cell disruption. Maximal up-regulation is induced by heat-stable bacterial cytoplasmic proteins, whereas NTHi surface membrane proteins induce only moderate MUC5AC transcription. These results demonstrate an important role for cytoplasmic molecules from lysed bacteria in the pathogenesis of NTHi infections, and may well explain why many patients still have persistent symptoms such as middle ear effusion in COME after intensive antibiotic treatment. Furthermore, our results indicate that activation of p38 mitogen-activated protein kinase is required for NTHi-induced MUC5AC transcription, whereas activation of phosphoinositide 3-kinase-Akt pathway leads to down-regulation of NTHi-induced MUC5AC transcription via a negative cross-talk with p38 mitogen-activated protein kinase pathway. These studies may bring new insights into molecular pathogenesis of NTHi infections and lead to novel therapeutic intervention for COME and COPD.
- Published
- 2002
22. Cell biology of tubotympanum in relation to pathogenesis of otitis media — a review
- Author
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Young-Myoung Chun, Sung-Kyun Moon, K. H. Chang, Ali Andalibi, Haa-Yung Lee, Jian Dong Li, and David J. Lim
- Subjects
Pulmonary Surfactant-Associated Proteins ,Tympanic Membrane ,beta-Defensins ,Eustachian tube ,Proteolipids ,Aquaporins ,Mice ,Immunity ,medicine ,Animals ,Homeostasis ,Humans ,Cilia ,Child ,Glycoproteins ,Innate immune system ,Pulmonary Surfactant-Associated Protein A ,General Veterinary ,General Immunology and Microbiology ,biology ,Lactoferrin ,Eustachian Tube ,Gene Expression Profiling ,Mucin ,Mucins ,Public Health, Environmental and Occupational Health ,Infant ,Epithelial Cells ,Pulmonary Surfactants ,Pulmonary Surfactant-Associated Protein D ,Acquired immune system ,Immunity, Innate ,Rats ,Mucus ,Otitis Media ,Infectious Diseases ,Otitis ,Beta defensin ,medicine.anatomical_structure ,Child, Preschool ,Immunology ,biology.protein ,Molecular Medicine ,Muramidase ,Disease Susceptibility ,Rabbits ,medicine.symptom - Abstract
The sterility of the eustachian tube and tympanic cavity of normal individuals is maintained not only by the adaptive immune system, but also by the mucociliary system and the antimicrobial molecules of innate immunity. Mucin production and periciliary fluid homeostasis are essential for normal mucociliary function and dysfunction of this system is an important risk factor for otitis media. The secreted antimicrobial molecules of the tubotympanum include lysozyme, lactoferrin, beta defensins, and the surfactant proteins A and D (SP-A, SP-D). Defects in the expression or regulation of these molecules may also be the major risk factor for otitis media.
- Published
- 2000
23. Lung Mucin Production Is Stimulated by the Air Pollutant Residual Oil Fly Ash
- Author
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Daizong Li, E. Matovinovic, Carol Basbaum, Jian Dong Li, James M. Samet, M. Gallup, and M. Longphre
- Subjects
Cytoplasm ,Cell signaling ,Lung Neoplasms ,Transcription, Genetic ,Bronchi ,Protein tyrosine phosphatase ,Biology ,Toxicology ,Cell Line ,chemistry.chemical_compound ,Downregulation and upregulation ,Tumor Cells, Cultured ,medicine ,Humans ,RNA, Messenger ,Particle Size ,Lung ,Pharmacology ,Air Pollutants ,Dose-Response Relationship, Drug ,Mucin ,Mucins ,Epithelial Cells ,Vanadium ,Mucus ,In vitro ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Lysozyme ,Fuel Oils ,Signal Transduction ,Respiratory tract - Abstract
Human and animal exposure to particulate air pollution is correlated with airway mucus hypersecretion and increased susceptibility to infection. Seeking clues to the mechanisms underlying this pathology, we examined the effect of the particulate air pollutant residual oil fly ash (ROFA) on production of the major component of mucus, mucin, and the major antibacterial protein of the respiratory tract, lysozyme. We found that following in vitro exposure to ROFA, epithelial cells showed an increase in mucin (MUC5AC) and lysozyme (LYS) steady state mRNA. This upregulation was controlled at least partly at the level of transcription as shown by reporter assays. Experiments testing the ability of the major components of ROFA to mimic these effects showed that vanadium, a metal making up 18.8% by weight, accounted for the bulk of the response. A screen of signaling inhibitors showed that MUC5AC and LYS induction by ROFA are mediated by dissimilar signaling pathways, both of which are, however, phosphotyrosine dependent. Recognizing that the ROFA constituent vanadium is a potent tyrosine phosphatase inhibitor and that mucin induction by pathogens is phophotyrosine dependent, we suggest that vanadium-containing air pollutants trigger disease-like conditions by unmasking phosphorylation-dependent pathogen resistance pathways.
- Published
- 2000
24. Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria
- Author
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Jay A. Nadel, Susumu Miyata, André Coste, C. Chapelin, Marianne Gallup, Carol Basbaum, Estelle Escudier, Austin F. Dohrman, and Jian Dong Li
- Subjects
Staphylococcus aureus ,Gram-negative bacteria ,Lipopolysaccharide ,Streptococcus pyogenes ,Bronchi ,In situ hybridization ,Mucin 5AC ,Gram-Positive Bacteria ,Cell Line ,Microbiology ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,Organ Culture Techniques ,0302 clinical medicine ,Downregulation and upregulation ,Pseudomonas ,Gram-Negative Bacteria ,Escherichia coli ,Staphylococcus epidermidis ,Humans ,RNA, Messenger ,Gene ,Molecular Biology ,030304 developmental biology ,Mucin-2 ,0303 health sciences ,biology ,Mucin overproduction ,Mucin ,Mucins ,Epithelial Cells ,biology.organism_classification ,Culture Media ,Up-Regulation ,3. Good health ,Gene Expression Regulation ,chemistry ,030220 oncology & carcinogenesis ,Mucin synthesis ,Molecular Medicine ,Mucin gene ,Bacterial infection ,Bacteria - Abstract
Bacterial infection of the lung is associated with mucin overproduction. In partial explanation of this phenomenon, we recently reported that supernatant from the Gram-negative organism Pseudomonas ( P .) aeruginosa contained an activity that upregulated transcription of the MUC 2 mucin gene [J.-D. Li, A. Dohrman, M. Gallup, S. Miyata, J. Gum, Y. Kim, J. Nadel, A. Prince, C. Basbaum, Transcriptional activation of mucin by P. aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease, Proc. Natl. Acad. Sci. U.S.A., 94 (1997) 967–972]. The purpose of the present study was to determine whether mucin genes other than MUC 2 are so regulated and whether Gram-positive organisms also contain mucin stimulatory activity. Results from in situ hybridization and RNase protection assays showed that P. aeruginosa upregulates MUC 5AC as well as MUC 2 in both bronchial explants and cultured airway epithelial cells. The upregulation of both genes by P. aeruginosa can be mimicked by lipopolysaccharide (LPS) and can be blocked by the tyrosine kinase inhibitor genistein. In addition, both genes are upregulated by a variety of Gram-positive as well as Gram-negative organisms showing the same rank order of potency. These data indicate the existence of a general mechanism by which epithelial cells respond to the presence of bacteria by increasing mucin synthesis.
- Published
- 1998
- Full Text
- View/download PDF
25. Sp1 protein contributes to airway-specific rat MUC 2 mucin gene transcription
- Author
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Hisamitsu Ohmori, Carol Basbaum, Hiroko Nogami, Jian Dong Li, Marianne Gallup, Young S. Kim, and James R. Gum
- Subjects
Cell type ,Transcription, Genetic ,Sp1 Transcription Factor ,Restriction Mapping ,Cell ,Biology ,Polymerase Chain Reaction ,Epithelium ,Genetics ,medicine ,Animals ,Cloning, Molecular ,Nuclear protein ,Promoter Regions, Genetic ,Cells, Cultured ,Mucin-2 ,Sp1 transcription factor ,Messenger RNA ,Binding Sites ,Base Sequence ,Mucin ,Mucins ,Nuclear Proteins ,General Medicine ,Transfection ,Molecular biology ,Rats ,DNA-Binding Proteins ,medicine.anatomical_structure ,Gene Expression Regulation ,Genes ,Cell culture ,Respiratory Physiological Phenomena - Abstract
We have shown increases in the abundance of airway mucin mRNA during the pathogenesis of chronic obstructive pulmonary disease in rat models ( Jany et al., 1991 ) and now seek to determine the underlying mechanisms. As transcriptional modulation may be involved, we provide here a functional analysis of the 5′ flanking region of a rat mucin gene (MUC 2). Using deletion mutants to bp −859, we constructed expression cassettes in CAT vectors and transfected them into two MUC 2-expressing cell lines, SPOC 1, a rat airway epithelial cell line and IEC-6, a rat intestinal epithelial cell line, and into one MUC 2 non-expressing cell line, FR, a rat skin fibroblast cell line. Results indicated that nucleotides −59 to −40 mediated high level expression in SPOC 1, but not in the other cells. Used as a probe in gel shift assays, fragment −59/−40 formed complexes of differing mobilities when incubated with nuclear protein extracts from the three cell types. Mutation of the putative Sp1 binding site in the probe sequence interfered with protein binding in all three cell types, but anti-Sp1 antibody supershifted a band formed only by airway cell extracts. A model of airway cell-specific MUC 2 transcription is proposed.
- Published
- 1997
26. A Preliminary Evaluation of Global and East Asian Cloud Radiative Effects in Reanalyses
- Author
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Jian-Dong, Li, primary and Jiang-Yu, Mao, additional
- Published
- 2015
- Full Text
- View/download PDF
27. Facial nerve hemangiomas: A review
- Author
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Zhi–yao, Song, primary and Jian–dong, Li, additional
- Published
- 2012
- Full Text
- View/download PDF
28. Electroretinographic b-wave merely reflects the activity of the rod system in the dark-adapted carp retina
- Author
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Xiong-Li, Yang, primary, Tian-Xing, Fan, additional, and Jian-Dong, Li, additional
- Published
- 1990
- Full Text
- View/download PDF
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