Transforming growth factor beta1 up-regulates interferon regulatory factor 8 during dendritic cell development.
Langerhans cells (LC) represent the cutaneous contingent of dendritic cells (DC). Their development critically depends on transforming growth factor beta1 (TGF-beta1) as demonstrated by analysis of TGF-beta1(-/-) mice, which lack LC. Here we used a two-step culture system and transcriptional profiling by DNA microarrays to search for TGF-beta1 target genes in DC. The study identified interferon regulatory factor 8 (IRF-8) as a novel target gene of TGF-beta1 signaling in DC. TGF-beta1 effectively induced Smad2/3 phosphorylation and IRF-8 RNA and protein expression. Blocking the TGF-beta1/Smad pathway by ectopic expression of inhibitory Smad7 and by SB431542 inhibitor abolished TGF-beta1 induced up-regulation of IRF-8. Furthermore, TGF-beta1-dependent induction of IRF-8 occurred in the absence of protein biosynthesis, suggesting a direct action of TGF-beta1/Smad signaling on IRF-8 gene activity. TGF-beta1 also induced expression of the chemokine receptor CCR7 and enhanced DC migration towards CCR7 ligand ELC. DC of IRF-8(-/-) mice show reduced CCR7 expression and migratory activity, thereby implicating the TGF-beta1/Smad/IRF-8 signaling pathway in CCR7 regulation. Thus, this study identified a novel TGF-beta1/Smad/IRF-8 signaling pathway with an impact on DC phenotype and function.
Ju
Xin-Sheng
XS
Institute for Biomedical Engineering, Department of Cell Biology, Aachen University Hospital, Aachen, Germany.
Ruau
David
D
Jäntti
Piritta
P
Seré
Kristin
K
Becker
Christiane
C
Wiercinska
Eliza
E
Bartz
Clemens
C
Erdmann
Bettina
B
Dooley
Steven
S
Zenke
Martin
M
D017951:Antigen Presentation / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D050835:Interferon Regulatory Factors / Q000276:immunology / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051785:Smad Proteins / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation; D000099185:Interferon Regulatory Factor-8
D050835:Interferon Regulatory Factors; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D000099185:Interferon Regulatory Factor-8; C515370:CCR7 protein, human