{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:17:07Z","timestamp":1790983027292,"version":"4.1.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T00:00:00Z","timestamp":1259625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sluggish was identified in a population of third generation mice descended from N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes exhibited impaired TNF-\u03b1 production in response to all TLR ligands tested and displayed impaired type I IFN production in response to TLR7 and TLR9 stimulations. The phenotype was confined to a critical region on mouse chromosome 18 and then ascribed to a T to A transversion in the acceptor splice site of intron 4 at position 13346 of the Map3k8 gene, resulting in defective splicing. The Map3k8Sluggish mutation does not result in susceptibility to viral infections, but Sluggish mice displayed high susceptibility to group B streptococcus infection, with impaired TNF-\u03b1 and type I IFN production in infected macrophages. Our data demonstrate that the encoded protein kinase Tpl2 plays an essential role in cell signaling in the immune response to certain pathogens.<\/jats:p>","DOI":"10.4049\/jimmunol.0902718","type":"journal-article","created":{"date-parts":[[2009,11,18]],"date-time":"2009-11-18T22:22:55Z","timestamp":1258582975000},"page":"7975-7983","source":"Crossref","is-referenced-by-count":29,"title":["The Tpl2 Mutation\n                    <i>Sluggish<\/i>\n                    Impairs Type I IFN Production and Increases Susceptibility to Group B Streptococcal Disease"],"prefix":"10.1093","volume":"183","author":[{"given":"Nengming","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Eidenschenk","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Krebs","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Brandl","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L","family":"Blasius","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Khovananth","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora G","family":"Smart","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Beutler","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,15]]},"reference":[{"key":"2026012811235430200_R1","first-page":"353","article-title":"Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.","volume-title":"Annu. 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Med.","year":"1996"},{"key":"2026012811235430200_R6","first-page":"457","article-title":"Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection.","volume-title":"Cell","year":"1993"},{"key":"2026012811235430200_R7","first-page":"227","article-title":"Cytokine appearance and effects of anti-tumor necrosis factor \u03b1 antibodies in a neonatal rat model of group B streptococcal infection.","volume-title":"Infect. Immun.","year":"1993"},{"key":"2026012811235430200_R8","first-page":"6324","article-title":"Dual role of TLR2 and myeloid differentiation factor 88 in a mouse model of invasive group B streptococcal disease.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811235430200_R9","first-page":"3126","article-title":"Type I IFN signaling is crucial for host resistance against different species of pathogenic bacteria.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811235430200_R10","first-page":"527","article-title":"Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes.","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2026012811235430200_R11","first-page":"437","article-title":"Type I interferon production enhances susceptibility to Listeria monocytogenes infection.","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2026012811235430200_R12","first-page":"535","article-title":"Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection.","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2026012811235430200_R13","first-page":"817","article-title":"Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase.","volume-title":"EMBO J.","year":"1996"},{"key":"2026012811235430200_R14","first-page":"2609","article-title":"Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-\u03baB.","volume-title":"Oncogene","year":"1998"},{"key":"2026012811235430200_R15","first-page":"1747","article-title":"Multiple mitogen-activated protein kinase signaling pathways connect the Cot oncoprotein to the c-jun promoter and to cellular transformation.","volume-title":"Mol. Cell. 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