Regulation of cell adhesion is important for immune system function. CD44 is a tightly regulated cell adhesion molecule present on Leukocytes and implicated in their attachment to endothelium during an inflammatory immune response. The proinflammatory cytokine tumor necrosis factor-alpha, but not interferon-gamma, was found to convert CD44 from its inactive, nonbinding form to its active form by inducing the sulfation of CD44. This posttranslational modification was required for CD44-mediated binding to the extracellular matrix component hyaluronan and to vascular endothelial cells. Sulfation is thus a potential means of regulating CD44-mediated Leukocyte adhesion at inflammatory sites.