title: Alternate transcription of the Toll-like receptor signaling cascade.
abstract: BACKGROUND
  Alternate splicing of key signaling molecules in the Toll-like receptor (Tlr) cascade has been shown to dramatically alter the signaling capacity of inflammatory cells, but it is not known how common this mechanism is. We provide transcriptional evidence of widespread alternate splicing in the Toll-like receptor signaling pathway, derived from a systematic analysis of the FANTOM3 mouse data set. Functional annotation of variant proteins was assessed in light of inflammatory signaling in mouse primary macrophages, and the expression of each variant transcript was assessed by splicing arrays.
  
  
  RESULTS
  A total of 256 variant transcripts were identified, including novel variants of Tlr4, Ticam1, Tollip, Rac1, Irak1, 2 and 4, Mapk14/p38, Atf2 and Stat1. The expression of variant transcripts was assessed using custom-designed splicing arrays. We functionally tested the expression of Tlr4 transcripts under a range of cytokine conditions via northern and quantitative real-time polymerase chain reaction. The effects of variant Mapk14/p38 protein expression on macrophage survival were demonstrated.
  
  
  CONCLUSIONS
  Members of the Toll-like receptor signaling pathway are highly alternatively spliced, producing a large number of novel proteins with the potential to functionally alter inflammatory outcomes. These variants are expressed in primary mouse macrophages in response to inflammatory mediators such as interferon-gamma and lipopolysaccharide. Our data suggest a surprisingly common role for variant proteins in diversification/repression of inflammatory signaling.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, School of Biological and Biomedical Sciences, Griffith University, Brisbane 4111, Australia. c.wells@griffith.edu.au
authors.forename: Christine A
authors.initials: CA
authors.lastname: Wells
authors.forename: Alistair M
authors.initials: AM
authors.lastname: Chalk
authors.forename: Alistair
authors.initials: A
authors.lastname: Forrest
authors.forename: Darrin
authors.initials: D
authors.lastname: Taylor
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.forename: S Roy
authors.initials: SR
authors.lastname: Himes
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Faulkner
authors.forename: Sandra
authors.initials: S
authors.lastname: Lo
authors.forename: Takeya
authors.initials: T
authors.lastname: Kasukawa
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.forename: Chikatoshi
authors.initials: C
authors.lastname: Kai
authors.forename: Jun
authors.initials: J
authors.lastname: Kawai
authors.forename: Shintaro
authors.initials: S
authors.lastname: Katayama
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017931:DNA Primers; D020869:Gene Expression Profiling; D014644:Genetic Variation; D016678:Genome; D008322:Mammals; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D051193:Toll-Like Receptors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors