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dc.contributor.authorMarchlik, Erica
dc.contributor.authorThakker, Paresh
dc.contributor.authorCarlson, Thaddeus
dc.contributor.authorJiang, Zhaozhao
dc.contributor.authorRyan, Mark
dc.contributor.authorMarusic, Suzana
dc.contributor.authorGoutagny, Nadege
dc.contributor.authorKuang, Wen
dc.contributor.authorAskew, G. Roger
dc.contributor.authorRoberts, Victoria
dc.contributor.authorBenoit, Stephen
dc.contributor.authorZhou, Tianhui
dc.contributor.authorLing, Vincent
dc.contributor.authorPfeifer, Richard
dc.contributor.authorStedman, Nancy
dc.contributor.authorFitzgerald, Katherine A.
dc.contributor.authorLin, Lih-Ling
dc.contributor.authorHall, J. Perry
dc.date2022-08-11T08:09:08.000
dc.date.accessioned2022-08-23T16:18:44Z
dc.date.available2022-08-23T16:18:44Z
dc.date.issued2010-12-24
dc.date.submitted2011-04-07
dc.identifier.citationJ Leukoc Biol. 2010 Dec;88(6):1171-80. Epub 2010 Jul 22. <a href="http://dx.doi.org/10.1189/jlb.0210071">Link to article on publisher's site</a>
dc.identifier.issn0741-5400 (Linking)
dc.identifier.doi10.1189/jlb.0210071
dc.identifier.pmid20651301
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34884
dc.description.abstractTBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Delta) allele encodes a truncated Tbk1(Delta) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Delta/Delta) mice produce normal levels of proinflammatory cytokines (e.g., TNF-alpha), but IFN-beta and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Delta/Delta) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/+) and Tbk1(+/Delta) littermates. Skin from 2-week-old Tbk1(Delta/Delta) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Delta/Delta) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Delta) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Delta/Delta) mice, including TNF-alpha, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Delta/Delta) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=20651301&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1189/jlb.0210071
dc.subjectAnimals
dc.subjectChemokine CCL2
dc.subjectFemale
dc.subjectInterferon Regulatory Factor-3
dc.subjectInterferon-beta
dc.subjectLipopolysaccharides
dc.subjectMale
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMonocytes
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectImmunology and Infectious Disease
dc.titleMice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality
dc.typeJournal Article
dc.source.journaltitleJournal of leukocyte biology
dc.source.volume88
dc.source.issue6
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/infdis_pp/112
dc.identifier.contextkey1924817
html.description.abstract<p>TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Delta) allele encodes a truncated Tbk1(Delta) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Delta/Delta) mice produce normal levels of proinflammatory cytokines (e.g., TNF-alpha), but IFN-beta and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Delta/Delta) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/+) and Tbk1(+/Delta) littermates. Skin from 2-week-old Tbk1(Delta/Delta) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Delta/Delta) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Delta) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Delta/Delta) mice, including TNF-alpha, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Delta/Delta) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.</p>
dc.identifier.submissionpathinfdis_pp/112
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages1171-80


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