154 Glucocorticoids promote inflammation by induction of CCL20 expression in keratinocytes

Glucocorticoids (GC) are widely used to treat autoimmune and inflammatory skin diseases and are generally envisioned as powerful immunosuppressants. However, in conditions such as rosacea and perioral dermatitis, GCs can paradoxically lead to increased skin inflammation. The molecular mechanisms by which GCs promote inflammation in these clinical contexts are not understood. Recently it was observed that GCs lead to increased expression of the pro-inflammatory cytokine, CCL20, in lung epithelia of steroid-resistant asthma. CCL20 is also expressed at high levels by keratinocytes in papulopustular rosacea, promoting inflammation by recruiting T-lymphocytes and dendritic cells. Here, we investigated how GCs affect CCL20 expression in human keratinocytes. In contrast to suppression of other pro-inflammatory cytokines, treatment of primary human keratinocytes with GCs led to 2 to 3-fold higher expression of CCL20. In addition, while GCs prevented the induction of inflammatory genes in response to tumor necrosis factor-α stimulation, CCL20 expression was amplified even further. Mechanistically, GCs repressed activity of inflammation-related signaling pathways including NFkB and p38/MAPK, but these inhibitory effects were counterbalanced by binding of activated glucocorticoid receptor to the CCL20 enhancer and promoter, which directly induced CCL20 expression. These results indicate that GCs directly promote CCL20 expression and provide new insight to how GCs may contribute to the inflammation observed in steroid-exacerbated and steroid-resistant skin conditions such as rosacea and perioral dermatitis.