Untersuchungen zur limitierten Proteolyse transmembraner Chemokine durch Disintegrin-ähnliche Metalloproteinasen
CX3CL1 (fractalkine) and CXCL16 are the only known chemokines so far which are expressed as membrane-bound molecules. Interestingly, their ectodomain can be cleaved off the cell-surface by the proteolytic activity of certain proteases, a process referred to as shedding. The identification of the proteases involved as well as a more detailed understanding of the function of the membrane-bound and soluble forms of CX3CL1 and CXCL16 was the objective of the study. It could be shown that both chemokines are upregulated by proinflammatory cytokines and shed by at least two members of the ADAM-family of disintegrin-like metalloproteinases, which are ADAM10 and ADAM17 (TACE). This finding was consistently supported by using selective ADAM-inhibitors and by comparing the shedding behaviour of CX3CL1 and CXCL16 in ADAM10-positive and -deficient cells. Static adhesion assays confirmed the involvement of CX3CL1 in leukocyte recruitment and pointed towards a role of CX3CL1-shedding for leukocyte diapedesis. Finally, for the first time, the presence of CXCL16 and its receptor CXCR6 in human brain was demonstrated, indicating a possible role for this chemokine in inflammatory processes of the brain.