CYLD Negatively Regulates Nontypeable Haemophilus influenzae-Induced IL-8 Expression via Phosphatase MKP-1-Dependent Inhibition of ERK
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{"title"=>"CYLD negatively regulates nontypeable haemophilus influenzae-induced IL-8 expression via phosphatase MKP-1-dependent inhibition of ERK", "type"=>"journal", "authors"=>[{"first_name"=>"Wenzhuo Y.", "last_name"=>"Wang", "scopus_author_id"=>"55276722400"}, {"first_name"=>"Kensei", "last_name"=>"Komatsu", "scopus_author_id"=>"25630937500"}, {"first_name"=>"Yuxian", "last_name"=>"Huang", "scopus_author_id"=>"54950804900"}, {"first_name"=>"Jing", "last_name"=>"Wu", "scopus_author_id"=>"56197132800"}, {"first_name"=>"Wenhong", "last_name"=>"Zhang", "scopus_author_id"=>"35279057300"}, {"first_name"=>"Ji Yun", "last_name"=>"Lee", "scopus_author_id"=>"37124481700"}, {"first_name"=>"Masanori", "last_name"=>"Miyata", "scopus_author_id"=>"55199499300"}, {"first_name"=>"Haidong", "last_name"=>"Xu", "scopus_author_id"=>"7407449143"}, {"first_name"=>"Jian Dong", "last_name"=>"Li", "scopus_author_id"=>"35248571600"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"25389768", "sgr"=>"84911363908", "pui"=>"600489386", "scopus"=>"2-s2.0-84911363908", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0112516"}, "id"=>"3d7afdc9-926f-33c0-84f8-59d72738b8a9", "abstract"=>"Nontypeable Haemophilus influenzae (NTHi), a Gram-negative bacterium, is the primary cause of otitis media in children and the exacerbation of chronic obstructive pulmonary disease in adults. A hallmark of both diseases is an overactive inflammatory response, including the upregulation of chemokines, such as interleukin-8 (IL-8). An appropriate inflammatory response is essential for eradicating pathogens. However, excessive inflammation can cause host tissue damage. Therefore, expression of IL-8 must be tightly regulated. We previously reported that NTHi induces IL-8 expression in an ERK-dependent manner. We also have shown that the deubiquitinase cylindromatosis (CYLD) suppresses NTHi-induced inflammation. However, the underlying molecular mechanism of how CYLD negatively regulates ERK-mediated IL-8 production is largely unknown. Here, we examine both human lung epithelial A549 cells and lung of Cyld-/- mice to show that CYLD specifically targets the activation of ERK. Interestingly, CYLD enhances NTHi-induced upregulation of another negative regulator, MAP Kinase Phosphatase-1 (MKP-1), which, in turn, leads to reduced ERK activation and subsequent suppression of IL-8. Taken together, the CYLD suppression of ERK-dependent IL-8 via MKP-1 may bring novel insights into the tight regulation of inflammatory responses and also lead to innovative therapeutic strategies for controlling these responses by targeting key negative regulators of inflammation.", "link"=>"http://www.mendeley.com/research/cyld-negatively-regulates-nontypeable-haemophilus-influenzaeinduced-il8-expression-via-phosphatase-m", "reader_count"=>7, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>3, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>3, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>2, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Computer Science"=>{"Computer Science"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1790981", "https://ndownloader.figshare.com/files/1790982"], "description"=>"<div><p>Nontypeable <i>Haemophilus influenzae</i> (NTHi), a Gram-negative bacterium, is the primary cause of otitis media in children and the exacerbation of chronic obstructive pulmonary disease in adults. A hallmark of both diseases is an overactive inflammatory response, including the upregulation of chemokines, such as interleukin-8 (IL-8). An appropriate inflammatory response is essential for eradicating pathogens. However, excessive inflammation can cause host tissue damage. Therefore, expression of IL-8 must be tightly regulated. We previously reported that NTHi induces IL-8 expression in an ERK-dependent manner. We also have shown that the deubiquitinase cylindromatosis (CYLD) suppresses NTHi-induced inflammation. However, the underlying molecular mechanism of how CYLD negatively regulates ERK-mediated IL-8 production is largely unknown. Here, we examine both human lung epithelial A549 cells and lung of <i>Cyld</i><sup>−/−</sup> mice to show that CYLD specifically targets the activation of ERK. Interestingly, CYLD enhances NTHi-induced upregulation of another negative regulator, MAP Kinase Phosphatase-1 (MKP-1), which, in turn, leads to reduced ERK activation and subsequent suppression of IL-8. Taken together, the CYLD suppression of ERK-dependent IL-8 via MKP-1 may bring novel insights into the tight regulation of inflammatory responses and also lead to innovative therapeutic strategies for controlling these responses by targeting key negative regulators of inflammation.</p></div>", "links"=>[], "tags"=>["novel insights", "ERK activation", "lung epithelial", "inflammation", "ERK Nontypeable Haemophilus influenzae", "549 cells", "mkp", "CYLD suppression", "MAP Kinase Phosphatase", "il", "response", "Otitis media", "deubiquitinase cylindromatosis", "host tissue damage"], "article_id"=>1238832, "categories"=>["Biological Sciences"], "users"=>["Wenzhuo Y. Wang", "Kensei Komatsu", "Yuxian Huang", "Jing Wu", "Wenhong Zhang", "Ji-Yun Lee", "Masanori Miyata", "Haidong Xu", "Jian-Dong Li"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0112516.s001", "https://dx.doi.org/10.1371/journal.pone.0112516.s002"], "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CYLD_Negatively_Regulates_Nontypeable_Haemophilus_influenzae_Induced_IL_8_Expression_via_Phosphatase_MKP_1_Dependent_Inhibition_of_ERK/1238832", "title"=>"CYLD Negatively Regulates Nontypeable <i>Haemophilus influenzae</i>-Induced IL-8 Expression via Phosphatase MKP-1-Dependent Inhibition of ERK", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-11-12 04:36:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1790972"], "description"=>"<p>(<b>A–B</b>) A549 cells transfected with (<b>A</b>) CYLD WT or (<b>B</b>) siCYLD were stimulated with NTHi for 5 h, and IL-8 mRNA expression was measured. (<b>C–D</b>) A549 cells transfected with IL-8 luciferase reporter gene and (<b>C</b>) CYLD WT or (<b>D</b>) siCYLD were stimulated with NTHi, and IL-8 transcriptional activity was measured by luciferase assay. (<b>E–F</b>) Cells transfected with (<b>E</b>) CYLD WT or (<b>F</b>) siCYLD were stimulated with NTHi for 12 h, and IL-8 protein in cell culture supernatants was measured by ELISA. (<b>G</b>) MIP-2, a mouse homologue of human IL-8, mRNA expression was measured in MEF cells from <i>Cyld<sup>+/+</sup></i> and <i>Cyld<sup>−/−</sup></i> mice stimulated with NTHi for 5 h. (<b>H</b>) MIP-2 mRNA expression was measured in lung tissues from <i>Cyld<sup>+/+</sup></i> and <i>Cyld<sup>−/−</sup></i> mice inoculated with NTHi. Data are mean ± SD (<i>n</i> = 3). *<i>p<0.05</i>. Statistical analysis was performed using Student's <i>t</i>-test. Data are representative of three or more independent experiments.</p>", "links"=>[], "tags"=>["novel insights", "ERK activation", "lung epithelial", "inflammation", "ERK Nontypeable Haemophilus influenzae", "549 cells", "mkp", "CYLD suppression", "MAP Kinase Phosphatase", "il", "response", "Otitis media", "deubiquitinase cylindromatosis", "host tissue damage"], "article_id"=>1238823, "categories"=>["Biological Sciences"], "users"=>["Wenzhuo Y. Wang", "Kensei Komatsu", "Yuxian Huang", "Jing Wu", "Wenhong Zhang", "Ji-Yun Lee", "Masanori Miyata", "Haidong Xu", "Jian-Dong Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112516.g001", "stats"=>{"downloads"=>4, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CYLD_negatively_regulates_NTHi_induced_IL_8_transcription_in_vitro_and_in_vivo_/1238823", "title"=>"CYLD negatively regulates NTHi-induced IL-8 transcription <i>in vitro</i> and <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-12 04:36:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1790973"], "description"=>"<p>(<b>A–B</b>) Cells transfected with (<b>A</b>) CYLD WT or (<b>B</b>) siCYLD were stimulated with NTHi for 30 min, and cell lysates were analyzed by immunoblotting with the indicated antibodies (upper panel). Phosphorylated ERK (pERK) protein expression was quantified (lower panel). (<b>B</b>) Cells transfected with siCON or siCYLD were stimulated with NTHi for 30 min, and cell lysates were analyzed by immunoblotting with the indicated antibodies. (<b>C</b>) MEF cells from <i>Cyld<sup>+/+</sup></i> and <i>Cyld<sup>−/−</sup></i> mice stimulated with NTHi for various times as indicated in the figure, and cell lysates were analyzed by immunoblotting with the indicated antibodies. Data are representative of three or more independent experiments.</p>", "links"=>[], "tags"=>["novel insights", "ERK activation", "lung epithelial", "inflammation", "ERK Nontypeable Haemophilus influenzae", "549 cells", "mkp", "CYLD suppression", "MAP Kinase Phosphatase", "il", "response", "Otitis media", "deubiquitinase cylindromatosis", "host tissue damage"], "article_id"=>1238825, "categories"=>["Biological Sciences"], "users"=>["Wenzhuo Y. Wang", "Kensei Komatsu", "Yuxian Huang", "Jing Wu", "Wenhong Zhang", "Ji-Yun Lee", "Masanori Miyata", "Haidong Xu", "Jian-Dong Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112516.g002", "stats"=>{"downloads"=>4, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CYLD_inhibits_NTHi_induced_activation_of_ERK_/1238825", "title"=>"CYLD inhibits NTHi-induced activation of ERK.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-12 04:36:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1790975"], "description"=>"<p>(<b>A</b>) A549 cells transfected with siCYLD were pretreated with PD98059 (20 µM) for 1 h, and IL-8 mRNA expression was measured after NTHi-stimulation. (<b>B</b>) Cells transfected with IL-8 luciferase reporter gene and siCYLD were pre-treated with PD98059 (20 µM) for 1 h, followed by NTHi-stimulation, and IL-8 transcriptional activity was measured by luciferase assay. (<b>C</b>) Cells transfected with siCYLD were pretreated with PD98059 (20 µM) for 1 h, followed by NTHi-stimulation, and IL-8 protein in the supernatants of cells was measured by ELISA. (<b>D–E</b>) Cells were transfected with MEK-CA and (<b>D</b>) CYLD WT or (<b>E</b>) siCYLD, and cell lysates were analyzed by immunoblotting with the indicated antibodies. (<b>F–G</b>) Cells were transfected with IL-8 luciferase reporter gene, MEK-CA and (<b>F</b>) CYLD WT or (<b>G</b>) siCYLD, and IL-8 transcriptional activity was measured. Data in <b>A–C, F</b> and <b>G</b> are mean ± SD (<i>n</i> = 3). *<i>p<0.05</i>. Statistical analysis was performed using Student's <i>t</i>-test. MEK-CA, constitutive active form of MEK. Data are representative of three or more independent experiments.</p>", "links"=>[], "tags"=>["novel insights", "ERK activation", "lung epithelial", "inflammation", "ERK Nontypeable Haemophilus influenzae", "549 cells", "mkp", "CYLD suppression", "MAP Kinase Phosphatase", "il", "response", "Otitis media", "deubiquitinase cylindromatosis", "host tissue damage"], "article_id"=>1238826, "categories"=>["Biological Sciences"], "users"=>["Wenzhuo Y. Wang", "Kensei Komatsu", "Yuxian Huang", "Jing Wu", "Wenhong Zhang", "Ji-Yun Lee", "Masanori Miyata", "Haidong Xu", "Jian-Dong Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112516.g003", "stats"=>{"downloads"=>7, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CYLD_negatively_regulates_NTHi_induced_IL_8_expression_via_inhibition_of_ERK_pathway_/1238826", "title"=>"CYLD negatively regulates NTHi-induced IL-8 expression via inhibition of ERK pathway.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-12 04:36:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1790977"], "description"=>"<p>(<b>A–B</b>) Cells transfected with (<b>A</b>) CYLD WT or (<b>B</b>) siCYLD were stimulated with NTHi for 1 h, and MKP-1 mRNA expression was measured. (<b>C</b>) MKP-1 mRNA expression was measured in lung tissues from <i>Cyld<sup>+/+</sup></i> and <i>Cyld<sup>−/−</sup></i> mice inoculated with NTHi. (<b>D</b>) Cells transfected with CYLD WT or DUB activity-deficient CYLD mutant (CYLD H/N) were stimulated with NTHi for 1 h, and MKP-1 mRNA expression was measured. (<b>E</b>) Cells transfected with CYLD WT or CYLD H/N were stimulated with NTHi for 5 h, and IL-8 mRNA expression was measured. Data are mean ± SD (<i>n</i> = 3). *<i>p<0.05</i>. Statistical analysis was performed using Student's <i>t</i>-test. n.s., nonsignificant. Data are representative of three or more independent experiments.</p>", "links"=>[], "tags"=>["novel insights", "ERK activation", "lung epithelial", "inflammation", "ERK Nontypeable Haemophilus influenzae", "549 cells", "mkp", "CYLD suppression", "MAP Kinase Phosphatase", "il", "response", "Otitis media", "deubiquitinase cylindromatosis", "host tissue damage"], "article_id"=>1238828, "categories"=>["Biological Sciences"], "users"=>["Wenzhuo Y. Wang", "Kensei Komatsu", "Yuxian Huang", "Jing Wu", "Wenhong Zhang", "Ji-Yun Lee", "Masanori Miyata", "Haidong Xu", "Jian-Dong Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112516.g004", "stats"=>{"downloads"=>0, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CYLD_is_a_positive_regulator_of_NTHi_induced_upregulation_of_MKP_1_expression_/1238828", "title"=>"CYLD is a positive regulator of NTHi-induced upregulation of MKP-1 expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-12 04:36:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1790978"], "description"=>"<p>(<b>A</b>) Cells transfected with IL-8 luciferase reporter gene, siCYLD and MKP-1 WT were stimulated with NTHi for 5 h, and IL-8 transcriptional activity was measured. (<b>B</b>) Cells transfected with siCYLD and MKP-1 WT were stimulated with NTHi for 30 min, and cell lysates were analyzed by immunoblotting with the indicated antibodies. (<b>C</b>) Cells transfected with IL-8 luciferase reporter gene, CYLD WT and shMKP-1 were stimulated with NTHi for 5 h, and IL-8 transcriptional activity was measured. (<b>D</b>) Cells transfected with CYLD WT and shMKP-1 were stimulated with NTHi for 30 min, and cell lysates were analyzed by immunoblotting with the indicated antibodies. Data in <b>A</b> and <b>C</b> are mean ± SD (<i>n</i> = 3). *<i>p<0.05</i>. Statistical analysis was performed using Student's <i>t</i>-test. Data are representative of three or more independent experiments.</p>", "links"=>[], "tags"=>["novel insights", "ERK activation", "lung epithelial", "inflammation", "ERK Nontypeable Haemophilus influenzae", "549 cells", "mkp", "CYLD suppression", "MAP Kinase Phosphatase", "il", "response", "Otitis media", "deubiquitinase cylindromatosis", "host tissue damage"], "article_id"=>1238829, "categories"=>["Biological Sciences"], "users"=>["Wenzhuo Y. Wang", "Kensei Komatsu", "Yuxian Huang", "Jing Wu", "Wenhong Zhang", "Ji-Yun Lee", "Masanori Miyata", "Haidong Xu", "Jian-Dong Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112516.g005", "stats"=>{"downloads"=>1, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CYLD_negatively_regulates_NTHi_induced_IL_8_expression_via_upregulating_MKP_1_/1238829", "title"=>"CYLD negatively regulates NTHi-induced IL-8 expression via upregulating MKP-1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-12 04:36:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1790979"], "description"=>"<p>As indicated, CYLD negatively regulates NTHi-induced IL-8 expression through MEK/ERK signaling pathway by upregulating phosphatase MKP-1.</p>", "links"=>[], "tags"=>["novel insights", "ERK activation", "lung epithelial", "inflammation", "ERK Nontypeable Haemophilus influenzae", "549 cells", "mkp", "CYLD suppression", "MAP Kinase Phosphatase", "il", "response", "Otitis media", "deubiquitinase cylindromatosis", "host tissue damage"], "article_id"=>1238831, "categories"=>["Biological Sciences"], "users"=>["Wenzhuo Y. Wang", "Kensei Komatsu", "Yuxian Huang", "Jing Wu", "Wenhong Zhang", "Ji-Yun Lee", "Masanori Miyata", "Haidong Xu", "Jian-Dong Li"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112516.g006", "stats"=>{"downloads"=>10, "page_views"=>352, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_model_illustrating_that_CYLD_negatively_regulates_NTHi_induced_IL_8_expression_via_MKP_1_dependent_inhibition_of_ERK_/1238831", "title"=>"Schematic model illustrating that CYLD negatively regulates NTHi-induced IL-8 expression via MKP-1-dependent inhibition of ERK.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-12 04:36:26"}

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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Cell biology", "average_usage"=>[286]}, {"subject_area"=>"/Biology and life sciences/Immunology", "average_usage"=>[293]}, {"subject_area"=>"/Medicine and health sciences/Immunology", "average_usage"=>[289]}, {"subject_area"=>"/Medicine and health sciences/Inflammatory diseases", "average_usage"=>[261, 415]}]}
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