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.