Inducible expression of a CC chemokine liver- and activation-regulated chemokine (LARC)/macrophage inflammatory protein (MIP)-3 alpha/CCL20 by epidermal keratinocytes and its role in atopic dermatitis

Liver- and activation-regulated chemokine (LARC)/macrophage inflammatory pr otein (MIP)3 alpha/ CCL20 is a CC chemokine which is constitutively express ed by follicle-associated epithelial cells in the mucosa, and attracts cell s expressing CCR6 such as immature dendritic cells and alpha (4)beta (high) (7) intestine-seeking memory T cells. Here, we examine LARC/CCL20 expressio n in the skin. LARC/CCL20 mRNA and protein were induced in primary human ke ratinocytes upon stimulation with proinflammatory cytokines such as IL-1 al pha and tumor necrosis factor (TNF)-alpha, In mice, intradermal injection o f IL-l a and TNF-a rapidly induced a local accumulation of transcripts for LARC/CCL20 and its receptor CCR6 with a lag of several hours in the latter. In humans, immunostaining of LARC/CCL20 was weak if any in normal skin tis sues but strongly augmented in lesional skin tissues with atopic dermatitis . Furthermore, massive infiltration of cells with markers such as CD1a, CD3 or HLA-DR was present in atopic skin lesions. Many infiltrating cells were also found to be CCR6(+) by a newly generated monoclonal anti-CCR6, Howeve r, Langerhans cells residing within the epidermis were hardly stained by an ti-CCR6 in normal and atopic skin tissues. Furthermore, plasma levels of LA RC/CCL20 were found to be elevated in patients with atopic dermatitis. Coll ectively, our results suggest that epidermal keratinocytes produce LARC/CCL 20 upon stimulation with proinflammatory cytokines such as IL-1 alpha and T NF-alpha, and attract CCR6-expressing immature dendritic cells and memory/e ffector T cells into the dermis of inflamed skin such as atopic dermatitis. LARC/CCL20 may not, however, play a major role in homeostatic migration of Langerhans cells into the skin.