Carboxypeptidase D: A Novel TGF-β Target Gene Dysregulated in Patients with Lupus Erythematosus

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that mainly acts as an inhibitor of immune functions. A lack of functional TGF-β leads to autoimmune disease in animal models and dysregulated TGF-β signaling is implicated in human autoimmune diseases. To define target genes that play a part in the inhibitory role of TGF-β in the immune system, we have identified genes stimulated by TGF-β in macrophages by gene-chip analysis. One of the TGF-β regulated genes is carboxypeptidase D (CpD), a 180-kDa type I membrane protein. We have demonstrated that CpD is regulated by TGF-β in various cell types of both, murine and human origin and, interestingly, is significantly downregulated in CD14 positive cells isolated from patients with lupus erythematosus (LE). Moreover, we show that downregulation of CpD leads to downmodulation of TGF-β itself, suggesting a role for CpD in a positive feedback loop, providing further evidence for a role of this enzyme in LE. To our knowledge, this is the first report that demonstrates carboxypeptidase D as a TGF-β target gene that is implicated in the pathogenesis of LE.