Cell-permeable ceramides act as novel regulators of U937 cell-cell adhesion mediated by CD29, CD98, and CD147

Ceramides are signaling molecules that regulate differentiation, proliferation, and apoptosis of cells. In this study, we report novel modulatory effects of ceramides on the functional activation of beta1 integrins (CD29) and their associated molecules, such as CD98 and CD147, using U937 cell-cell or cell-fibronectin (FN) adhesion events. Cell-permeable ceramides (C2- or C6-ceramides) effectively blocked monocytic cell-cell adhesion, mediated by CD29, CD98, and CD147, and cell-FN adhesion in a dose-dependent manner. The suppressive effect was demonstrated with the treatment of only ceramides but not other sphingolipid metabolites or analogs, such as sphingosine, dihydrosphingosine, and fumonisin B1. Ceramides displayed a distinct inhibitory profile on cell-cell and cell-FN adhesions compared with other inhibitors such as PD98059 (an extracellular signal-related kinase (ERK) inhibitor), SB203580 (a p38 inhibitor), rottlerin (a PKCdelta inhibitor), and cytochalasin B (an actin cytoskeleton disruptor). Interestingly, C6-ceramide inhibited the phosphorylation of CD29 induced by MEM101A treatment and down-regulated surface levels of CD29, CD98, and CD147, as well as CD49d. Since there are no reports showing that ceramides act as negative regulators of the functional activation of CD29, our results therefore suggest a novel possibility that ceramides can be used as a therapeutic drug regarding CD29-mediated pathological events, including tumor metastasis, inflammatory states, granuloma formation, and blood vessel occlusion.