Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C
To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells. In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibite...
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| Veröffentlicht in: | Inflammation research 2005-07, Vol.54 (7), p.304-312 |
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| creator | Sandler, C Ekokoski, E Lindstedt, K A Vainio, P J Finel, M Sorsa, T Kovanen, P T Golub, L M Eklund, K K |
| description | To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells.
In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3% of control. Similarly, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 microM CMT-3 to 13.5 +/- 4.1% and 9.7 +/- 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC(50) value of 31 microM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity.
Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders. |
| doi_str_mv | 10.1007/s00011-005-1358-5 |
| format | Article |
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In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3% of control. Similarly, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 microM CMT-3 to 13.5 +/- 4.1% and 9.7 +/- 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC(50) value of 31 microM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity.
Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.</description><identifier>ISSN: 1023-3830</identifier><identifier>EISSN: 1420-908X</identifier><identifier>DOI: 10.1007/s00011-005-1358-5</identifier><identifier>PMID: 16134060</identifier><language>eng</language><publisher>Switzerland: Springer Nature B.V</publisher><subject>Animals ; Antigens, CD34 - biosynthesis ; Brain - metabolism ; Carcinogens ; Cell Line, Tumor ; Cells, Cultured ; Cloning, Molecular ; Cytokines - biosynthesis ; Cytokines - metabolism ; Dose-Response Relationship, Drug ; Fetal Blood ; Histamine - metabolism ; Histamine Release ; Humans ; Inflammation ; Interleukin-8 - metabolism ; Male ; Mast Cells - cytology ; Mast Cells - metabolism ; Phorbol 12,13-Dibutyrate - pharmacology ; Protein Kinase C - metabolism ; Protein Kinase C - physiology ; Protein Kinase C-alpha ; Protein Kinase C-delta ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - metabolism ; Tetracyclines - pharmacology ; Time Factors ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Inflammation research, 2005-07, Vol.54 (7), p.304-312</ispartof><rights>Birkhäuser Verlag, Basel 2005</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c357t-60a377e0f3e75975c543385751d1855a22cf363679c20d179c23f3a4b643dafe3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16134060$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sandler, C</creatorcontrib><creatorcontrib>Ekokoski, E</creatorcontrib><creatorcontrib>Lindstedt, K A</creatorcontrib><creatorcontrib>Vainio, P J</creatorcontrib><creatorcontrib>Finel, M</creatorcontrib><creatorcontrib>Sorsa, T</creatorcontrib><creatorcontrib>Kovanen, P T</creatorcontrib><creatorcontrib>Golub, L M</creatorcontrib><creatorcontrib>Eklund, K K</creatorcontrib><title>Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C</title><title>Inflammation research</title><addtitle>Inflamm Res</addtitle><description>To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells.
In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3% of control. Similarly, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 microM CMT-3 to 13.5 +/- 4.1% and 9.7 +/- 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC(50) value of 31 microM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity.
Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.</description><subject>Animals</subject><subject>Antigens, CD34 - biosynthesis</subject><subject>Brain - metabolism</subject><subject>Carcinogens</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>Cloning, Molecular</subject><subject>Cytokines - biosynthesis</subject><subject>Cytokines - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Fetal Blood</subject><subject>Histamine - metabolism</subject><subject>Histamine Release</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Interleukin-8 - metabolism</subject><subject>Male</subject><subject>Mast Cells - cytology</subject><subject>Mast Cells - metabolism</subject><subject>Phorbol 12,13-Dibutyrate - pharmacology</subject><subject>Protein Kinase C - metabolism</subject><subject>Protein Kinase C - physiology</subject><subject>Protein Kinase C-alpha</subject><subject>Protein Kinase C-delta</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - metabolism</subject><subject>Tetracyclines - pharmacology</subject><subject>Time Factors</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>1023-3830</issn><issn>1420-908X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkU-L1TAUxYMozh_9AG4kuBBdRG9ym6Z1J8VRYcTNCO5CXnrLy9g2zyYdeJ_DL2zKeyC4uuHmdw7nchh7IeGdBDDvEwBIKQC0kKgboR-xS1kpEC00Px-XNygU2CBcsKuU7gvdqEY9ZReyllhBDZfsT7enKXg3jkc-xT4MgXqeKS_OH_0YZuJvum93bwXyMO_DLuTE9yFlN21fC43kEnE399wfc_y1LQ9L7FefQ5yLhE8uZe5pHNMHfogphd1IZf8QxweaaM48DpsiU2GLfHPrnrEngxsTPT_Pa_bj5tNd90Xcfv_8tft4Kzxqk0UNDo0hGJCMbo32ukJstNGyl43WTik_YI21ab2CXm4DB3TVrq6wdwPhNXt98i0Bfq-Usp1C2rK6meKarAJoTWOqAr76D7yP6zKXbFbJWmErpSqQPEF-KXcuNNjDEia3HK0Eu9VlT3XZUpfd6rK6aF6ejdfdRP0_xbkf_AsBVJD5</recordid><startdate>200507</startdate><enddate>200507</enddate><creator>Sandler, C</creator><creator>Ekokoski, E</creator><creator>Lindstedt, K A</creator><creator>Vainio, P J</creator><creator>Finel, M</creator><creator>Sorsa, T</creator><creator>Kovanen, P T</creator><creator>Golub, L M</creator><creator>Eklund, K K</creator><general>Springer Nature B.V</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>7QL</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>200507</creationdate><title>Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C</title><author>Sandler, C ; Ekokoski, E ; Lindstedt, K A ; Vainio, P J ; Finel, M ; Sorsa, T ; Kovanen, P T ; Golub, L M ; Eklund, K K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c357t-60a377e0f3e75975c543385751d1855a22cf363679c20d179c23f3a4b643dafe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Antigens, CD34 - 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In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3% of control. Similarly, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 microM CMT-3 to 13.5 +/- 4.1% and 9.7 +/- 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC(50) value of 31 microM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity.
Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.</abstract><cop>Switzerland</cop><pub>Springer Nature B.V</pub><pmid>16134060</pmid><doi>10.1007/s00011-005-1358-5</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Antigens, CD34 - biosynthesis Brain - metabolism Carcinogens Cell Line, Tumor Cells, Cultured Cloning, Molecular Cytokines - biosynthesis Cytokines - metabolism Dose-Response Relationship, Drug Fetal Blood Histamine - metabolism Histamine Release Humans Inflammation Interleukin-8 - metabolism Male Mast Cells - cytology Mast Cells - metabolism Phorbol 12,13-Dibutyrate - pharmacology Protein Kinase C - metabolism Protein Kinase C - physiology Protein Kinase C-alpha Protein Kinase C-delta Rats Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - metabolism Tetracyclines - pharmacology Time Factors Tumor Necrosis Factor-alpha - metabolism |
| title | Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C |
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