MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana
In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2...
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| creator | Al-Mutairi, Mashael S Cadalbert, Laurence C McGachy, H Adrienne Shweash, Muhannad Schroeder, Juliane Kurnik, Magdalena Sloss, Callum M Bryant, Clare E Alexander, James Plevin, Robin |
| description | In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2(+/+) but not from MKP-2(-/-) mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2(-/-) macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE(2) production. However surprisingly, in MKP-2(-/-) macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2(-/-) mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2(-/-) T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2(-/-) bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage. |
| doi_str_mv | 10.1371/journal.ppat.1001192 |
| format | Article |
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Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2(+/+) but not from MKP-2(-/-) mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2(-/-) macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE(2) production. However surprisingly, in MKP-2(-/-) macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2(-/-) mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2(-/-) T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2(-/-) bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1001192</identifier><identifier>PMID: 21085614</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Arginase - metabolism ; Blotting, Western ; Bone marrow ; Bone Marrow - immunology ; Bone Marrow - metabolism ; Bone Marrow - pathology ; Cell Biology/Cell Signaling ; Cells, Cultured ; Cellular signal transduction ; Cytokines - metabolism ; Enzymes ; Experiments ; Female ; Gene expression ; Genetic aspects ; Immune response ; Immune system ; Immunology/Immunity to Infections ; Infections ; Infectious Diseases/Tropical and Travel-Associated Diseases ; Inflammation Mediators - metabolism ; Kinases ; Leishmania ; Leishmania mexicana ; Leishmania mexicana - pathogenicity ; Leishmaniasis, Cutaneous - immunology ; Leishmaniasis, Cutaneous - metabolism ; Leishmaniasis, Cutaneous - prevention & control ; Lipopolysaccharides - pharmacology ; Macrophages - immunology ; Macrophages - metabolism ; Macrophages - pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mitogen-activated protein kinases ; Nitric oxide ; Nitric Oxide - metabolism ; p38 Mitogen-Activated Protein Kinases - metabolism ; Parasites ; Phosphorylation ; Physiological aspects ; Protein Tyrosine Phosphatases - physiology ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Rodents ; Studies ; Th1 Cells - immunology ; Th1 Cells - metabolism ; Th2 Cells - immunology ; Th2 Cells - metabolism</subject><ispartof>PLoS pathogens, 2010-11, Vol.6 (11), p.e1001192-e1001192</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>Al-Mutairi et al. 2010</rights><rights>2010 Al-Mutairi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Al-Mutairi MS, Cadalbert LC, McGachy HA, Shweash M, Schroeder J, et al. (2010) MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana. PLoS Pathog 6(11): e1001192. doi:10.1371/journal.ppat.1001192</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c730t-256c2b8effcb14ff83c749e24509eb9b511c5f5a255e286fc2d1db13ee756a243</citedby><cites>FETCH-LOGICAL-c730t-256c2b8effcb14ff83c749e24509eb9b511c5f5a255e286fc2d1db13ee756a243</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/PMC2978729/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978729/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21085614$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Müller, Ingrid</contributor><creatorcontrib>Al-Mutairi, Mashael S</creatorcontrib><creatorcontrib>Cadalbert, Laurence C</creatorcontrib><creatorcontrib>McGachy, H Adrienne</creatorcontrib><creatorcontrib>Shweash, Muhannad</creatorcontrib><creatorcontrib>Schroeder, Juliane</creatorcontrib><creatorcontrib>Kurnik, Magdalena</creatorcontrib><creatorcontrib>Sloss, Callum M</creatorcontrib><creatorcontrib>Bryant, Clare E</creatorcontrib><creatorcontrib>Alexander, James</creatorcontrib><creatorcontrib>Plevin, Robin</creatorcontrib><title>MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2(+/+) but not from MKP-2(-/-) mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2(-/-) macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE(2) production. However surprisingly, in MKP-2(-/-) macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2(-/-) mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2(-/-) T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2(-/-) bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage.</description><subject>Animals</subject><subject>Arginase - metabolism</subject><subject>Blotting, Western</subject><subject>Bone marrow</subject><subject>Bone Marrow - immunology</subject><subject>Bone Marrow - metabolism</subject><subject>Bone Marrow - pathology</subject><subject>Cell Biology/Cell Signaling</subject><subject>Cells, Cultured</subject><subject>Cellular signal transduction</subject><subject>Cytokines - metabolism</subject><subject>Enzymes</subject><subject>Experiments</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunology/Immunity to Infections</subject><subject>Infections</subject><subject>Infectious Diseases/Tropical and Travel-Associated Diseases</subject><subject>Inflammation Mediators - metabolism</subject><subject>Kinases</subject><subject>Leishmania</subject><subject>Leishmania mexicana</subject><subject>Leishmania mexicana - pathogenicity</subject><subject>Leishmaniasis, Cutaneous - immunology</subject><subject>Leishmaniasis, Cutaneous - metabolism</subject><subject>Leishmaniasis, Cutaneous - prevention & control</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Knockout</subject><subject>Mitogen-activated protein kinases</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Parasites</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Protein Tyrosine Phosphatases - physiology</subject><subject>Proteins</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Rodents</subject><subject>Studies</subject><subject>Th1 Cells - immunology</subject><subject>Th1 Cells - metabolism</subject><subject>Th2 Cells - immunology</subject><subject>Th2 Cells - metabolism</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVktmO0zAUhiMEYoaBN0AQiQvERYuPl8S-QapGLJXKIpZbLMc5aV2SONgJmr49Lu2MphISQr7w9v3_0Vmy7DGQObASXm79FHrTzofBjHMgBEDRO9k5CMFmJSv53Vvns-xBjFtCODAo7mdnFIgUBfDz7Pv7xaf8h-tNxHzY-DhszJjOM5oPrdnF3OQ2uNFZ0-bBt5i7Pg8YB98nfvTp2qAdne_zapev0MVNZ3pn8g6vkqY3D7N7jWkjPjruF9m3N6-_Xr6brT6-XV4uVjNbMjLOqCgsrSQ2ja2AN41ktuQKKRdEYaUqAWBFIwwVAqksGktrqCtgiKUoDOXsInt68B1aH_WxNFEDlQqo4CATsTwQtTdbPQTXmbDT3jj958GHtTYhJdqilhUrCeMceSW5UFQljxoLToTkaHEf7dUx2lR1WFvsx2DaE9PTn95t9Nr_0lSVsqQqGTw_GgT_c8I46s5Fi21revRT1Apk6hXQ4p-kJJIXUCiayGcHcm1SDqkxPoW2e1ovUoUKxhUniZr_hUqrxs5Z32Pj0vuJ4MWJIDEjXo1rM8Wol18-_wf74ZTlB9YGH2PA5qZ8QPR-wK-7qPcDro8DnmRPbpf-RnQ90ew3uSv13Q</recordid><startdate>20101101</startdate><enddate>20101101</enddate><creator>Al-Mutairi, Mashael S</creator><creator>Cadalbert, Laurence C</creator><creator>McGachy, H Adrienne</creator><creator>Shweash, Muhannad</creator><creator>Schroeder, Juliane</creator><creator>Kurnik, Magdalena</creator><creator>Sloss, Callum M</creator><creator>Bryant, Clare E</creator><creator>Alexander, James</creator><creator>Plevin, Robin</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>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>M7N</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20101101</creationdate><title>MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana</title><author>Al-Mutairi, Mashael S ; Cadalbert, Laurence C ; McGachy, H Adrienne ; Shweash, Muhannad ; Schroeder, Juliane ; Kurnik, Magdalena ; Sloss, Callum M ; Bryant, Clare E ; Alexander, James ; Plevin, Robin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c730t-256c2b8effcb14ff83c749e24509eb9b511c5f5a255e286fc2d1db13ee756a243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Arginase - metabolism</topic><topic>Blotting, Western</topic><topic>Bone marrow</topic><topic>Bone Marrow - immunology</topic><topic>Bone Marrow - metabolism</topic><topic>Bone Marrow - pathology</topic><topic>Cell Biology/Cell Signaling</topic><topic>Cells, Cultured</topic><topic>Cellular signal transduction</topic><topic>Cytokines - metabolism</topic><topic>Enzymes</topic><topic>Experiments</topic><topic>Female</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunology/Immunity to Infections</topic><topic>Infections</topic><topic>Infectious Diseases/Tropical and Travel-Associated Diseases</topic><topic>Inflammation Mediators - metabolism</topic><topic>Kinases</topic><topic>Leishmania</topic><topic>Leishmania mexicana</topic><topic>Leishmania mexicana - pathogenicity</topic><topic>Leishmaniasis, Cutaneous - immunology</topic><topic>Leishmaniasis, Cutaneous - metabolism</topic><topic>Leishmaniasis, Cutaneous - prevention & control</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophages - immunology</topic><topic>Macrophages - metabolism</topic><topic>Macrophages - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Knockout</topic><topic>Mitogen-activated protein kinases</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - metabolism</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Parasites</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Protein Tyrosine Phosphatases - physiology</topic><topic>Proteins</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>Rodents</topic><topic>Studies</topic><topic>Th1 Cells - immunology</topic><topic>Th1 Cells - metabolism</topic><topic>Th2 Cells - immunology</topic><topic>Th2 Cells - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Al-Mutairi, Mashael S</creatorcontrib><creatorcontrib>Cadalbert, Laurence C</creatorcontrib><creatorcontrib>McGachy, H Adrienne</creatorcontrib><creatorcontrib>Shweash, Muhannad</creatorcontrib><creatorcontrib>Schroeder, Juliane</creatorcontrib><creatorcontrib>Kurnik, Magdalena</creatorcontrib><creatorcontrib>Sloss, Callum M</creatorcontrib><creatorcontrib>Bryant, Clare E</creatorcontrib><creatorcontrib>Alexander, James</creatorcontrib><creatorcontrib>Plevin, Robin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Al-Mutairi, Mashael S</au><au>Cadalbert, Laurence C</au><au>McGachy, H Adrienne</au><au>Shweash, Muhannad</au><au>Schroeder, Juliane</au><au>Kurnik, Magdalena</au><au>Sloss, Callum M</au><au>Bryant, Clare E</au><au>Alexander, James</au><au>Plevin, Robin</au><au>Müller, Ingrid</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2010-11-01</date><risdate>2010</risdate><volume>6</volume><issue>11</issue><spage>e1001192</spage><epage>e1001192</epage><pages>e1001192-e1001192</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2(+/+) but not from MKP-2(-/-) mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2(-/-) macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE(2) production. However surprisingly, in MKP-2(-/-) macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2(-/-) mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2(-/-) T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2(-/-) bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21085614</pmid><doi>10.1371/journal.ppat.1001192</doi><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Public Library of Science (PLoS); PubMed Central |
| subjects | Animals Arginase - metabolism Blotting, Western Bone marrow Bone Marrow - immunology Bone Marrow - metabolism Bone Marrow - pathology Cell Biology/Cell Signaling Cells, Cultured Cellular signal transduction Cytokines - metabolism Enzymes Experiments Female Gene expression Genetic aspects Immune response Immune system Immunology/Immunity to Infections Infections Infectious Diseases/Tropical and Travel-Associated Diseases Inflammation Mediators - metabolism Kinases Leishmania Leishmania mexicana Leishmania mexicana - pathogenicity Leishmaniasis, Cutaneous - immunology Leishmaniasis, Cutaneous - metabolism Leishmaniasis, Cutaneous - prevention & control Lipopolysaccharides - pharmacology Macrophages - immunology Macrophages - metabolism Macrophages - pathology Male Mice Mice, Inbred BALB C Mice, Knockout Mitogen-activated protein kinases Nitric oxide Nitric Oxide - metabolism p38 Mitogen-Activated Protein Kinases - metabolism Parasites Phosphorylation Physiological aspects Protein Tyrosine Phosphatases - physiology Proteins Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Rodents Studies Th1 Cells - immunology Th1 Cells - metabolism Th2 Cells - immunology Th2 Cells - metabolism |
| title | MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana |
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