title: Bruton's tyrosine kinase together with PI 3-kinase are part of Toll-like receptor 2 multiprotein complex and mediate LTA induced Toll-like receptor 2 responses in macrophages.
abstract: Lipoteichoic acid (LTA) of Gram-positive bacteria initiates innate immune responses via Toll-like receptor-2 (TLR2), resulting in the activation of intracellular signaling and production of inflammatory cytokines in macrophages. Although Bruton's tyrosine kinase (Btk) is biologically important molecule implicated in immune regulation and recently in TLR signaling its importance for LTA-TLR2 mediated responses has not been evaluated. In this study, we detected Btk in the LTA signaling complex with TLR2 and PI 3-kinase (PI3K). The constitutive interaction of these proteins was mediated via PI3K Src homology (SH3) -domain. Both Btk and PI3K were activated by LTA stimulation and the LTA induced cytokine expression was differentially modulated by these kinases. LTA induced the activation of nuclear factor kappaB (NFkappaB), however, only Btk inhibition affected the LTA induced Ser536 phosphorylation and DNA-binding of NFkappaB. In conclusion, our results demonstrate that Btk and PI3K occupy important roles in TLR2-induced activation of macrophages, resulting in selective regulation of cytokines.
authors.affiliation: Department of Pediatrics, Biocenter Oulu, P.O. Box 5000, FIN-90014, University of Oulu, Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Liljeroos
authors.forename: R
authors.initials: R
authors.lastname: Vuolteenaho
authors.forename: S
authors.initials: S
authors.lastname: Morath
authors.forename: T
authors.initials: T
authors.lastname: Hartung
authors.forename: M
authors.initials: M
authors.lastname: Hallman
authors.forename: M
authors.initials: M
authors.lastname: Ojaniemi
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002460:Cell Line; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C009900:lipoteichoic acid; D008156:Luciferases; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse