Identification of TTP mRNA targets in human dendritic cells reveals TTP as a critical regulator of dendritic cell maturation.
Dendritic cells provide a critical link between innate and adaptive immunity and are essential to prime a naive T-cell response. The transition from immature dendritic cells to mature dendritic cells involves numerous changes in gene expression; however, the role of post-transcriptional changes in this process has been largely ignored. Tristetraprolin is an AU-rich element mRNA-binding protein that has been shown to regulate the stability of a number of cytokines and chemokines of mRNAs. Using TTP immunoprecipitations and Affymetrix GeneChips, we identified 393 messages as putative TTP mRNA targets in human dendritic cells. Gene ontology analysis revealed that approximately 25% of the identified mRNAs are associated with protein synthesis. We also identified six MHC Class I alleles, five MHC Class II alleles, seven chemokine and chemokine receptor genes, indoleamine 2,3 dioxygenase, and CD86 as putative TTP ligands. Real-time PCR was used to validate the GeneChip data for 15 putative target genes and functional studies performed for six target genes. These data establish that TTP regulates the expression of DUSP1, IDO, SOD2, CD86, and MHC Class I-B and F via the 3'-untranslated region of each gene. A novel finding is the demonstration that TTP can interact with and regulate the expression of non-AU-rich element-containing messages. The data implicate TTP as having a broader role in regulating and limiting the immune response than previously suspected.
Emmons
Jillian
J
Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Townley-Tilson
W H Davin
WH
Deleault
Kristen M
KM
Skinner
Stephen J
SJ
Gross
Robert H
RH
Whitfield
Michael L
ML
Brooks
Seth A
SA
D020413:3' Untranslated Regions; D051940:B7-2 Antigen / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018925:Chemokines / Q000235:genetics; D004247:DNA / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D017930:Genes, Reporter; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D008024:Ligands; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D051816:Tristetraprolin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*
D020413:3' Untranslated Regions; D051940:B7-2 Antigen; C497964:CD86 protein, human; D018925:Chemokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008024:Ligands; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D004247:DNA