Transcytosis and Surface Presentation of IL-8 by Venular Endothelial Cells

Abstract

Chemokines have been convincingly implicated in actuating inflammatory leukocyte emigration. To affect the circulating leukocytes, tissue-derived chemokines have to traverse the endothelial cells (ECs). This was thought to be accomplished by chemokine diffusion through the intercellular gaps. On the contrary, we show by electron microscopy that the prototype chemokine IL-8 is internalized by venular ECs abluminally and transcytosed to the luminal surface. Here, it is presented to the adherent leukocytes on the EC membrane, predominantly in association with the EC projections. The intact C terminus of IL-8, the molecule's "immobilization" domain, is required for the EC binding, transcytosis, and consequently, the in vivo proemigratory activity of IL-8, indicating that the described subcellular interactions of IL-8 with the ECs are functionally relevant.

Examination of MCP-1 (CCL2) partitioning and presentation during transendothelial leukocyte migration

“…50 However, the focal distribution of MCP-1 observed on the apical cell surface is unlikely to be related to discharge of transport vesicles, as a similar pattern of focal chemokine distribution was observed following apical application of MCP-1.…”

Induction of a CXCL8 binding site on endothelial syndecan‐3 in rheumatoid synovium

“…It is also apparent that syndecan core proteins may be involved in forming membrane rafts, concentrating ligands in membrane microdomains and internalizing ligands in vesicles (6,(67)(68)(69). Chemokine transcytosis and presentation by endothelial cells involve plasmalemmal vesicles (caveolae) and membrane microdomains (the tips of endothelial microvilli) (13,31,70), which suggests a potential role for syndecans in these mechanisms.…”

“…An increasing body of evidence supports the functional importance of chemokine-HS interactions in the process of leukocyte migration from the blood into inflamed tissues (13,(30)(31)(32). Data suggest an involvement of HS in the transcytosis of chemokines across endothelial cells.…”

“…This results in leukocyte activation and migration across the endothelium and into the tissue. The functional importance of chemokine-HS interactions has been shown in vivo, because administration of modified chemokines that exhibit reduced affinity to HS or heparin resulted in diminished leukocyte recruitment (31,32). Other functions of glycosaminoglycan-chemokine interactions have been proposed, including the formation of immobilized chemokine gradients in the extracellular matrix and the protection of these mediators from degradation, resulting in the prolongation of their activities (15,35,36).…”

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

“…The chemokine regulation by DARC may be indispensable as indicated by its' broad distribution on endothelial cells (ECs), even in Duffy negative individuals who lack the erythrocyte receptor (Peiper et al, 1995). Immunoelectronic microscopy studies have demonstrated that chemokines injected into the skin in vivo or ex vivo were internalized by ECs and detected in intracellular transport caveloae compartment, later shown to contain Duffy antigen (Chaudhuri et al, 1997;Middleton et al, 1997). Du et al (2002) observed that Duffy antigen downmodulates the angiogenic effect of CXC chemokines in transgenic mice.…”