Importance of CD109 and Transforming Growth Factor-β Signaling in Psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, leukocyte infiltration, and alterations in cytokine production. Recent work documented that the inappropriately activated T helper cells 1 and 17 lymphocytes play a critical role in disease initiation and progression by elaborating an array of inflammatory cytokines that deregulate normal keratinocyte proliferation and differentiation. The key signal to suppress keratinocyte growth is the transforming growth factor (3 (TGF-β) protein, the expression of which is documented to be increased in psoriatic patients. Despite the observed upregulation in TGF-β signal, psoriatic keratinocytes continue to proliferate in response to other signals. Thus, there appears to be discordance between high levels of TGF-β at a lesion site and increased keratinocyte growth. Recently we identified CD109, a glycosyl-phosphatidylinositol (GPI)-anchored protein, as a novel regulator of the TGF-β signaling. CD109 is expressed on the keratinocyte cell surface and is released via an endogenous lipase into the extracellular milieu. Membrane-anchored CD109 has been documented to bind the TGF-β protein as well as interact with the TGF-β receptor and alter its stability and function. We describe here the paradoxical discordance between high TGF-β levels and the lack of proliferation inhibition in psoriatic skin. We also highlight the possible importance of CD109 as a critical TGF-β signaling modulator in psoriasis. Further understanding of CD109 and TGF-β signaling in psoriasis may lead to development of new, effective therapies.