Tissue-specific differences between endothelia : expression and presentation of chemokines and their receptors

Hillyer, Philippa (2003). Tissue-specific differences between endothelia : expression and presentation of chemokines and their receptors. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f6f9


The recruitment of different leukocyte subpopulations during an inflammatory response is regulated by various molecules expressed by the endothelium. This study examines how chemokine production, the expression of chemokine receptors and the binding of chemokines to the proteoglycan layer vary between endothelia from different vascular beds.
Human dermal, lung and liver endothelia were compared with endothelia derived from saphenous and umbilical veins and with a transformed bone marrow cell line. All endothelia produced MCP-1 (CCL2) and IL-8 (CXCL8) constitutively with both these chemokines and IP-10 (CXCL10) and RANTES (CCL5) being secreted after TNF-aor IFN-y stimulation, whereas MlP-1a (CCL3) was not produced under any conditions tested. A combination of TNF-a and IFN-y stimulation increased RANTES and IP-10 production, but reduced IL-8 production. The addition of TGF-p reduced secretion of all chemokines. Differences were found in production levels of each of these chemokines depending on the tissue that the endothelial cells were derived from. MIP-1a, and RANTES bound to the cell surface of each endothelium tested at differing levels, but IP-10 bound only to lung endothelium. RANTES binding was found to be dependent on the presence of Heparan Sulphate Proteoglycan (HSPG), but MIP-1a appeared to bind via a different method. Chemokine receptors CXCR1, CXCR3 and CCR3 were expressed highly at the endothelial cell surface, with lower levels of CXCR2, CXCR4, CXCR5, OCRS and CCR6. Expression of CCR4 varied widely. Using lectins to identify specific oligosaccharides, differences in the composition of the proteoglycan layer were probed. Small variations were shown, but these cannot account for the differences in chemokine binding.
These results demonstrate that endothelial cells could be important in the selective recruitment of leukocytes to different tissues, in particular in their expression of chemokines in response to inflammatory stimuli and their presentation of chemokines to the leukocytes In the blood stream.

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