Proteinase-mediated release of epithelial cell-associated CD44 -: Extracellular CD44 complexes with components of cellular matrices

CD44 is a receptor for the matrix glycosaminoglycan hyaluronan. Proteoglycan forms of CD44 also exhibit affinity for fibronectin and collagen as well as chemokines and growth factors. CD44 plays a role in autoimmunity, inflammation, and tumor progression. Soluble CD44 (sCD44) is found in plasma, and the levels of sCD44 correlate with immune function and some malignancies. The mechanisms by which sCD44 is generated and its function are unknown. We demonstrate here that normal bronchial epithelial cells spontaneously release sCD44. Exposure to phagocyte- and bacterium-derived proteinases markedly increased the release of sCD44 from epithelial cells. The spontaneously released sCD44 was incorporated into high molecular mass complexes derived from the matrix that also contained chondroitin sulfate, fibronectin, hyaluronan, and collagens I and IV. Enzymatic digestion with proteinases liberated sCD44 from the high molecular mass complex. Consistent with the homology of CD44 to proteoglycan core and link proteins, these data suggest that CD44 spontaneously released from normal bronchial epithelial cells can accumulate as an integral component of the matrix, where it may play a role in the organization of matrices and in anchoring growth factors and chemokines to the matrix. Increases in plasma CD44 during immune activation and tumor progression therefore may be a manifestation of the matrix remodeling that occurs in the face of the enhanced proteolytic activity associated with infection, inflammation, and tumor metastasis, leading to alterations in cell-matrix interactions.