IMPLICATION OF CD44 IN ADHESION-MEDIATED OVERPRODUCTION OF TGF-BETA AND IL-1 IN MONOCYTES FROM PATIENTS WITH BONE-MARROW FIBROSIS

Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis and e xcessive deposits of extracellular matrix (ECM) proteins which include fibronectin (FN), collagen type I and hyaluronic acid (HA), We have p reviously reported that adhesion to polystyrene over-activates MF mono cytes. We now confirm their activation by increased CD25 expression an d tyrosine phosphorylation, We hypothesize that ECM protein-adhesion m olecule interactions induce overproduction of fibrogenic cytokines in MF monocytes leading to BM fibrosis. In this study we found that FN, c ollagen type I and HA induce 2-3-fold more TGF-beta and 6-9-fold more interleukin (IL)-1 in MF monocytes than normal controls (NC). Since CD 44 can function as the natural ligand for these proteins, its role was studied. We found that CD44 mediated most of the TGF-beta and IL-1 pr oduced, Immunoprecipitation of CD44 revealed three proteins at approxi mately 110 kD in MF monocytes and one in NC. Our results indicate that adhesion is important in overproduction of TGF-beta and IL-1, and tha t their production is at least partly mediated by adhesion molecule-EC M protein interactions, These results implicate at least one adhesion molecule, CD44, in the pathophysiology of BM fibrosis.