Constitutive Expression and Regulated Release of the Transmembrane Chemokine CXCL16 in Human

The CXC-chemokine ligand 16 (CXCL16) is expressed as a transmembrane adhesion molecule and can bereleased as a chemoattractant. Both functions are carried out by binding of CXCL16 to its receptor, CXC-chemokine receptor 6 (CXCR6). We here provide early evidence that CXCL16 is expressed in situby epidermalkeratinocytes of normal skin on messenger RNA and protein level and released into the wound exudate uponinjury.Cultured human and murine keratinocyte cell lines (HaCaT and PAM212, respectively) as well as primarykeratinocyte cultures constitutively express transmembrane CXCL16 on the cell surface. Soluble CXCL16 isreleased by its limited proteolytic cleavage involving the disintegrin-like metalloproteinase (ADAM)10 but notthe closely related ADAM17, as shown by specific inhibitors and small-interfering RNA knockdownexperiments. This shedding of CXCL16 is reduced by serum starvation but enhanced by cell stimulation withionomycin or by UVB irradiation. Soluble CXCL16 from keratinocytes was shown to bind and activate CXCR6,and marked expression of this receptor was found on a subpopulation of T cells in the dermis. Thus, CXCL16 isconstitutively expressed on the surface of human epidermal keratinocytes, released upon cell activation orphotodamage and may then target CXCR6-expressing T cells in the dermis.