During inflammation, monocytic ?4?1 integrins associate with vascular cell adhesion molecule 1 (VCAM-1) on the surface of endothelial cells. This event is known to be crucial for monocye transmigration through the vascular wall under normal physiological conditions as well as during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, allergy, and transplant-rejection. For this reason, inhibition of this interaction is studied as a therapeutic approach to inflammation and autoimmune diseases. In differentiating promonocytic cells, the downregulation of the trans-golgi enzyme, ST6Gal I, leads to the expression of hyposialylated 01 integrins. Based on this evidence, it is necessary to determine if ?4?1 hyposialylation plays a key role in regulating monocyte adhesion to the endothelium. Preliminary data show that: 1) the expression of hyposialylated ?1 integrins is temporally correlated with enhanced VCAM-1 binding, 2) inhibiting ?4?1 integrin hyposialylation eliminates VCAM-1 binding, 3) VCAM-1 binding, like the expression of hyposialylated integrins, is regulated by a PKC/ras/ERK signaling cascade and 4) Alzheimer's ?-secretase (BACE1) expression, a protease known to cleave ST6Gal I, is upregulated upon differentiation. ? ? ?
