Cyclic AMP and tumor necrosis factor-alpha regulate CXCR4 gene expression in Schwann cells.

Rat peripheral nerve Schwann cells have been shown to express the alpha-chemokine receptor CXCR4 as well as the corresponding ligand stromal cell-derived factor-1 (SDF-1). We have investigated gene regulatory mechanisms acting on the expression of CXCR4 in cultured rat Schwann cells and found that receptor expression at transcript- and protein levels is directly dependent on intracellular cyclic AMP. Such increased levels of CXCR4 expression were found to be efficiently reversed by the action of tumor necrosis factor-alpha (TNFalpha). We also provide evidence that the POU box transcription factor Oct-6/SCIP is involved in the control of CXCR4 transcription. Finally, we could demonstrate that CXCR4 activation by SDF-1alpha increases the number of dying Schwann cells, indicating that this receptor/ligand interaction is modulating cell survival. Our data, therefore, suggest that in the Schwann cell lineage signal transduction cascades controlled by the activation of TNF- and CXCR4 receptors are functionally coupled.