Cerebral cell adhesion molecule: a novel leukocyte adhesion determinant on blood-brain barrier capillary endothelium.

The tight junctions of the cerebral capillary endothelium form the highly restrictive blood-brain barrier. Migration of leukocytes across this unique barrier may involve ligation of elements in addition to those of the fenestrated capillaries of the peripheral vascular system. An antibody raised against a bacterial adhesive protein and shown to have cross-reactivity with brain capillaries and to block leukocyte migration into the brain was used to identify and clone a novel determinant on brain microvessels. This cDNA was sequenced, and the expressed protein supported leukocyte adhesion in a CD18-dependent fashion. The high level of brain microvessel expression of this adhesion molecule, termed the cerebral cell adhesion molecule, implicates it in leukocyte transmigration across the blood-brain barrier.

Coexistence of CD14-dependent and independent pathways for stimulation of human monocytes by gram-positive bacteria.

The cell wall is a key inflammatory agent of gram-positive bacteria. Possible receptors mediating cell wall-induced inflammation include CD14 and platelet-activating factor (PAF) receptor. To delineate the conditions under which these various receptors might be used, human monocytic THP-1 cells and heparinized whole human blood were stimulated with lipopolysaccharide (LPS), intact Streptococcus pneumoniae bacteria, or purified pneumococcal cell wall. THP-1 culture supernatant or cell-free plasma was analyzed for the presence of tumor necrosis factor, interleukin-1beta (IL-1beta), and IL-6. For the cultured monocytes, anti-CD14 inhibited induction of the inflammatory cytokines by the cell wall and LPS but not by intact pneumococcal bacteria. Despite the difference in CD-14 usage, the intracellular pathways induced by the three agents demonstrated similarities, as revealed in the presence of specific signal transduction inhibitors such as cholera toxin, pertussis toxin, and genistein. Cytokine production in whole human blood indicated that anti-CD14 failed to block responses to cell wall and intact pneumococci, whereas while LPS-induced responses were inhibited. PAF receptor antagonist had no effect under any conditions in both assays. These results indicate that although cell walls bind to both CD14 and PAF receptor, only CD14 appears to engender a cytokine response under restricted conditions. Furthermore, host cell responses to intact pneumococci are consistently independent of CD14 and PAF receptor.