Ca2+/calmodulin-dependent kinase kinase alpha is expressed by monocytic cells and regulates the activation profile
Macrophages are capable of assuming numerous phenotypes in order to adapt to endogenous and exogenous challenges but many of the factors that regulate this process are still unknown. We report that Ca(2+)/calmodulin-dependent kinase kinase alpha (CaMKKalpha) is expressed in human monocytic cells and...
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| description | Macrophages are capable of assuming numerous phenotypes in order to adapt to endogenous and exogenous challenges but many of the factors that regulate this process are still unknown. We report that Ca(2+)/calmodulin-dependent kinase kinase alpha (CaMKKalpha) is expressed in human monocytic cells and demonstrate that its inhibition blocks type-II monocytic cell activation and promotes classical activation. Affinity chromatography with paramagnetic beads isolated an approximately 50 kDa protein from nuclear lysates of U937 human monocytic cells activated with phorbol-12-myristate-13-acetate (PMA). This protein was identified as CaMKKalpha by mass spectrometry and Western analysis. The function of CaMKKalpha in monocyte activation was examined using the CaMKKalpha inhibitors (STO-609 and forskolin) and siRNA knockdown. Inhibition of CaMKKalpha, enhanced PMA-dependent CD86 expression and reduced CD11b expression. In addition, inhibition was associated with decreased translocation of CaMKKalpha to the nucleus. Finally, to further examine monocyte activation profiles, TNFalpha and IL-10 secretion were studied. CaMKKalpha inhibition attenuated PMA-dependent IL-10 production and enhanced TNFalpha production indicating a shift from type-II to classical monocyte activation. Taken together, these findings indicate an important new role for CaMKKalpha in the differentiation of monocytic cells. |
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We report that Ca(2+)/calmodulin-dependent kinase kinase alpha (CaMKKalpha) is expressed in human monocytic cells and demonstrate that its inhibition blocks type-II monocytic cell activation and promotes classical activation. Affinity chromatography with paramagnetic beads isolated an approximately 50 kDa protein from nuclear lysates of U937 human monocytic cells activated with phorbol-12-myristate-13-acetate (PMA). This protein was identified as CaMKKalpha by mass spectrometry and Western analysis. The function of CaMKKalpha in monocyte activation was examined using the CaMKKalpha inhibitors (STO-609 and forskolin) and siRNA knockdown. Inhibition of CaMKKalpha, enhanced PMA-dependent CD86 expression and reduced CD11b expression. In addition, inhibition was associated with decreased translocation of CaMKKalpha to the nucleus. Finally, to further examine monocyte activation profiles, TNFalpha and IL-10 secretion were studied. CaMKKalpha inhibition attenuated PMA-dependent IL-10 production and enhanced TNFalpha production indicating a shift from type-II to classical monocyte activation. Taken together, these findings indicate an important new role for CaMKKalpha in the differentiation of monocytic cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0001606</identifier><identifier>PMID: 18270593</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetic acid ; Active Transport, Cell Nucleus ; Affinity chromatography ; Animal sciences ; Antigens, CD - analysis ; Beads ; Calcium ; Calcium-binding protein ; Calcium-Calmodulin-Dependent Protein Kinase Kinase - analysis ; Calcium-Calmodulin-Dependent Protein Kinase Kinase - antagonists & inhibitors ; Calcium-Calmodulin-Dependent Protein Kinase Kinase - physiology ; Calmodulin ; CD11b antigen ; CD86 antigen ; Cell activation ; Cell Biology/Cell Signaling ; Cell Biology/Leukocyte Signaling and Gene Expression ; Cell Differentiation ; Cells, Cultured ; Chromatography ; Cytokines ; Dendritic cells ; Enzyme Inhibitors - pharmacology ; Epidermal growth factor ; Forskolin ; Humans ; Immunology ; Immunology/Leukocyte Activation ; Immunology/Leukocyte Signaling and Gene Expression ; Inhibition ; Interleukin 10 ; Interleukin-10 - biosynthesis ; Kinases ; Leukemia ; Lysates ; Macrophages ; Mass spectrometry ; Mass spectroscopy ; Monocytes ; Monocytes - chemistry ; Monocytes, Activated Killer ; Phosphorylation ; Proteins ; siRNA ; Studies ; Tetradecanoylphorbol Acetate - pharmacology ; Translocation ; Tumor Necrosis Factor-alpha - biosynthesis ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2008-02, Vol.3 (2), p.e1606</ispartof><rights>2008 Guest et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Guest et al. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-8b392ebc099c80853b236cd8e95064e6b9e2db81f8a0a75b377ea6527b7101d93</citedby><cites>FETCH-LOGICAL-c454t-8b392ebc099c80853b236cd8e95064e6b9e2db81f8a0a75b377ea6527b7101d93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229650/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229650/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18270593$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guest, Christopher B</creatorcontrib><creatorcontrib>Deszo, Eric L</creatorcontrib><creatorcontrib>Hartman, Matthew E</creatorcontrib><creatorcontrib>York, Jason M</creatorcontrib><creatorcontrib>Kelley, Keith W</creatorcontrib><creatorcontrib>Freund, Gregory G</creatorcontrib><title>Ca2+/calmodulin-dependent kinase kinase alpha is expressed by monocytic cells and regulates the activation profile</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Macrophages are capable of assuming numerous phenotypes in order to adapt to endogenous and exogenous challenges but many of the factors that regulate this process are still unknown. We report that Ca(2+)/calmodulin-dependent kinase kinase alpha (CaMKKalpha) is expressed in human monocytic cells and demonstrate that its inhibition blocks type-II monocytic cell activation and promotes classical activation. Affinity chromatography with paramagnetic beads isolated an approximately 50 kDa protein from nuclear lysates of U937 human monocytic cells activated with phorbol-12-myristate-13-acetate (PMA). This protein was identified as CaMKKalpha by mass spectrometry and Western analysis. The function of CaMKKalpha in monocyte activation was examined using the CaMKKalpha inhibitors (STO-609 and forskolin) and siRNA knockdown. Inhibition of CaMKKalpha, enhanced PMA-dependent CD86 expression and reduced CD11b expression. In addition, inhibition was associated with decreased translocation of CaMKKalpha to the nucleus. Finally, to further examine monocyte activation profiles, TNFalpha and IL-10 secretion were studied. CaMKKalpha inhibition attenuated PMA-dependent IL-10 production and enhanced TNFalpha production indicating a shift from type-II to classical monocyte activation. Taken together, these findings indicate an important new role for CaMKKalpha in the differentiation of monocytic cells.</description><subject>Acetic acid</subject><subject>Active Transport, Cell Nucleus</subject><subject>Affinity chromatography</subject><subject>Animal sciences</subject><subject>Antigens, CD - analysis</subject><subject>Beads</subject><subject>Calcium</subject><subject>Calcium-binding protein</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Kinase - analysis</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Kinase - antagonists & inhibitors</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Kinase - physiology</subject><subject>Calmodulin</subject><subject>CD11b antigen</subject><subject>CD86 antigen</subject><subject>Cell activation</subject><subject>Cell Biology/Cell Signaling</subject><subject>Cell Biology/Leukocyte Signaling and Gene Expression</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Chromatography</subject><subject>Cytokines</subject><subject>Dendritic cells</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epidermal growth factor</subject><subject>Forskolin</subject><subject>Humans</subject><subject>Immunology</subject><subject>Immunology/Leukocyte Activation</subject><subject>Immunology/Leukocyte Signaling and Gene Expression</subject><subject>Inhibition</subject><subject>Interleukin 10</subject><subject>Interleukin-10 - biosynthesis</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Lysates</subject><subject>Macrophages</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Monocytes</subject><subject>Monocytes - chemistry</subject><subject>Monocytes, Activated Killer</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>siRNA</subject><subject>Studies</subject><subject>Tetradecanoylphorbol Acetate - pharmacology</subject><subject>Translocation</subject><subject>Tumor Necrosis Factor-alpha - biosynthesis</subject><subject>Tumor necrosis factor-α</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1kktv1DAUhS0EomXgHyCwxLLK1I_YcTZI1YhCpUpsYG35cTPjwRMHO6mYf0_KpNAuWF3Lvue710cHobeUrClv6OU-Tbk3cT2kHtaEECqJfIbOactZJRnhzx-dz9CrUvaECK6kfInOqGINES0_R3lj2MWlM_GQ_BRDX3kYoPfQj_hH6E2Bh2LisDM4FAy_hgylgMf2iA-pT-44BocdxFiw6T3OsJ2iGaHgcTfr3BjuzBhSj4ecuhDhNXrRmVjgzVJX6Pv1p2-bL9Xt1883m6vbytWiHitlecvAOtK2ThEluGVcOq-gFUTWIG0LzFtFO2WIaYTlTQNGCtbYhhLqW75C70_cIaaiF7uKppwyqgSdzVihm1OHT2avhxwOJh91MkH_uUh5q02ePxdBC_BNzYj0XcNrUI0ltvacGqk6z5ivZ9bHZdpkD-Dd7GA28Qn06Usfdnqb7jRjrJWCzIAPCyCnnxOU8T8r16cul1MpGbq_EyjR97l4UOn7XOglF7Ps3ePt_omWIPDf_MG3-w</recordid><startdate>20080213</startdate><enddate>20080213</enddate><creator>Guest, Christopher B</creator><creator>Deszo, Eric L</creator><creator>Hartman, Matthew E</creator><creator>York, Jason M</creator><creator>Kelley, Keith W</creator><creator>Freund, Gregory G</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20080213</creationdate><title>Ca2+/calmodulin-dependent kinase kinase alpha is expressed by monocytic cells and regulates the activation profile</title><author>Guest, Christopher B ; Deszo, Eric L ; Hartman, Matthew E ; York, Jason M ; Kelley, Keith W ; Freund, Gregory G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c454t-8b392ebc099c80853b236cd8e95064e6b9e2db81f8a0a75b377ea6527b7101d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Acetic acid</topic><topic>Active Transport, Cell Nucleus</topic><topic>Affinity chromatography</topic><topic>Animal sciences</topic><topic>Antigens, CD - analysis</topic><topic>Beads</topic><topic>Calcium</topic><topic>Calcium-binding protein</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Kinase - analysis</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Kinase - antagonists & inhibitors</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Kinase - physiology</topic><topic>Calmodulin</topic><topic>CD11b antigen</topic><topic>CD86 antigen</topic><topic>Cell activation</topic><topic>Cell Biology/Cell Signaling</topic><topic>Cell Biology/Leukocyte Signaling and Gene Expression</topic><topic>Cell Differentiation</topic><topic>Cells, Cultured</topic><topic>Chromatography</topic><topic>Cytokines</topic><topic>Dendritic cells</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epidermal growth factor</topic><topic>Forskolin</topic><topic>Humans</topic><topic>Immunology</topic><topic>Immunology/Leukocyte Activation</topic><topic>Immunology/Leukocyte Signaling and Gene Expression</topic><topic>Inhibition</topic><topic>Interleukin 10</topic><topic>Interleukin-10 - 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We report that Ca(2+)/calmodulin-dependent kinase kinase alpha (CaMKKalpha) is expressed in human monocytic cells and demonstrate that its inhibition blocks type-II monocytic cell activation and promotes classical activation. Affinity chromatography with paramagnetic beads isolated an approximately 50 kDa protein from nuclear lysates of U937 human monocytic cells activated with phorbol-12-myristate-13-acetate (PMA). This protein was identified as CaMKKalpha by mass spectrometry and Western analysis. The function of CaMKKalpha in monocyte activation was examined using the CaMKKalpha inhibitors (STO-609 and forskolin) and siRNA knockdown. Inhibition of CaMKKalpha, enhanced PMA-dependent CD86 expression and reduced CD11b expression. In addition, inhibition was associated with decreased translocation of CaMKKalpha to the nucleus. Finally, to further examine monocyte activation profiles, TNFalpha and IL-10 secretion were studied. CaMKKalpha inhibition attenuated PMA-dependent IL-10 production and enhanced TNFalpha production indicating a shift from type-II to classical monocyte activation. Taken together, these findings indicate an important new role for CaMKKalpha in the differentiation of monocytic cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>18270593</pmid><doi>10.1371/journal.pone.0001606</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Acetic acid Active Transport, Cell Nucleus Affinity chromatography Animal sciences Antigens, CD - analysis Beads Calcium Calcium-binding protein Calcium-Calmodulin-Dependent Protein Kinase Kinase - analysis Calcium-Calmodulin-Dependent Protein Kinase Kinase - antagonists & inhibitors Calcium-Calmodulin-Dependent Protein Kinase Kinase - physiology Calmodulin CD11b antigen CD86 antigen Cell activation Cell Biology/Cell Signaling Cell Biology/Leukocyte Signaling and Gene Expression Cell Differentiation Cells, Cultured Chromatography Cytokines Dendritic cells Enzyme Inhibitors - pharmacology Epidermal growth factor Forskolin Humans Immunology Immunology/Leukocyte Activation Immunology/Leukocyte Signaling and Gene Expression Inhibition Interleukin 10 Interleukin-10 - biosynthesis Kinases Leukemia Lysates Macrophages Mass spectrometry Mass spectroscopy Monocytes Monocytes - chemistry Monocytes, Activated Killer Phosphorylation Proteins siRNA Studies Tetradecanoylphorbol Acetate - pharmacology Translocation Tumor Necrosis Factor-alpha - biosynthesis Tumor necrosis factor-α |
| title | Ca2+/calmodulin-dependent kinase kinase alpha is expressed by monocytic cells and regulates the activation profile |
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