Ischemic stroke in a major territory, which was proven in all stroke patients by repeated cranial imaging, is always associated with a severe breakdown of the BBB 24 h after onset. Therefore, a release of sJAM-A, if present, should have been detectable in patients with stroke. Based on our results it appears that sJAM-A is not suited as a serum biomarker for BBB breakdown in humans, which is in contrast to vascular cell adhesion molecule-1. Soluble VCAM-1 serum levels were reported to positively correlate in MS patients with clinical disease activity and an inflammatory BBB breakdown as indicated by Gadolinium-enhancing MRI lesions. Furthermore, enhanced serum levels of soluble VCAM-1 were reported in patients with ischemic stroke. Soluble VCAM-1 is released from HBMEC upon pro-inflammatory stimulation through a marimastat-inhibitable process, probably reflecting ADAM17 activation as demonstrated in murine EC. JAM-A was found to be shedded from HUVEC by ADAM10 and 17. The cited studies in brain EC indicate that differences of inducible sJAM release under pro-inflammatory conditions between HBMEC and HUVEC are rather not due to differential ADAM17 activation in both cell types. The reason for a differential release of sJAM-A upon inflammatory stimulation of different EC types currently Semaxanib remains unknown. Given that brain EC exhibit particularly strong barrier properties protecting the CNS, our results of a missing inducible sJAM-A release under pro-inflammatory conditions might somehow challenge the view that sJAM-A blocks leukocyte extravasation in vivo under pathophysiological conditions, as suggested by studies using recombinant JAM-A in vitro and in vivo. Of note and in contrast to sJAM-A, the expression of cell-bound JAMA in brain EC upon inflammatory stimulation in vitro is regulated as previously described in other EC types. It is well established that altered expression of cell-bound JAM-A under inflammatory conditions may facilitate leukocyte extravasation. If the inducible release of sJAM-A under pro-inflammatory conditions really serves to limit leukocyte extravasation in vivo it is surprising that an EC type known for its strong barrier properties does not exhibit this inflammation-limiting feature while at least in vitro JAM-A functions allowing leukocyte extravasation, i.e. redistribution to the cell surface under inflammatory conditions, seem to function like in other vascular beds. In summary, we demonstrated that the regulation of JAM-A cell surface expression and the release of sJAM-A by both primary and immortalized human brain endothelium share some features with EC types from other parts of the body but also show unique properties of brain EC, not described in other EC types so far.