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Overlapping Signaling Pathways of Sphingosine 1-Phosphate and TGF- in the Murine Langerhans Cell Line XS52¹

Heinfried H. Radeke^*, Henrik von Wenckstern, Kirsten Stoidtner^*, Bettina Sauer, Stefanie Hammer and Burkhard Kleuser^2,

^* pharmazentrum frankfurt, Clinic of the Johann Wolfgang Goethe-University, Frankfurt/Main, Germany; and Institute of Pharmacy, Free University Berlin, Berlin, Germany

TGF- has been defined as a key mediator for the induction and maintenance of immunological tolerance. Concomitantly, it is essential for homeostasis of specialized epithelial dendritic cells, namely, Langerhans cells (LC). Our data reveal that TGF- induces migration of the immature LC, XS52, a cell line expressing the signaling components, TGF- type I and II receptors and Smad2, 3, and 4 mRNA. TGF- stimulation induced transient Smad3/4 oligomerization and Smad3/DNA binding. Antisense oligonucleotides (ASO) targeting Smad3 abrogated TGF--induced XS52 chemotaxis, proving the involvement of this Smad protein in the TGF--dependent migration. In contrast, the typical CCR6-dependent chemotaxis of immature LC induced by CCL20/MIP-3 was not affected by Smad3 ASO. Most notably, we also identified the lysophospholipid sphingosine 1-phosphate (S1P) as a potent chemoattractant for immature LC, which expressed mRNA transcripts of lysophospholipid receptors S1P_1–4. Additional experiments with specific ASO showed that the G_i-coupled receptors S1P₁ and S1P₃ were dominantly involved in the S1P-induced migration. In contrast, lysophosphatidic acid (LPA), also binding to members of the lysophospholipid receptor family, failed to induce XS52 migration. Intriguingly, we raised evidence that TGF- and S1P signal transduction pathways are indeed overlapping, as S1P augmented Smad activation and targeted DNA binding with kinetics comparable to TGF-. Finally, S1P failed to stimulate XS52 chemotaxis when Smad3 protein expression was abrogated. Thus, our data indicate a cross-communication between S1P and TGF- signaling that might be relevant for more than only migratory activities of immature LC.

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