MONOCYTE ADHESION IN PATIENTS WITH BONE-MARROW FIBROSIS IS REQUIRED FOR THE PRODUCTION OF FIBROGENIC CYTOKINES - POTENTIAL ROLE FOR INTERLEUKIN-1 AND TGF-BETA

Idiopathic myelofibrosis (IMF) is a hemologic disorder characterized b y bone marrow (BM) fibrosis. The BM contains excessive deposits of ext racellular matrix proteins and exhibits neovascularization. The fibros is is hypothesized to be a reactive phenomenon secondary to a clonal m yeloid disorder. Growth factors such as platelet-derived growth factor (PDGF), TGF-beta, and epidermal growth factor have been postulated as potential agents involved in BM fibrosis. We studied the induction of two fibrogenic cytokines, IL-1 and TGF-beta, in IMF monocytes. High l evels of both cytokines were produced in unstimulated IMF monocytes, c ompared with background levels produced in normal controls. Most of th e TGF-beta produced by IMF monocytes was in its active form. The spont aneous induction of IL-1 alpha, IL-1 beta, and TGF-beta in IMF monocyt es parallels an increase in their steady state mRNA. Although high lev els of cytoplasmic IL-1 alpha, IL-1 beta, and TGF-beta protein were de tected in monocytes that were not subjected to any form of adherence, the secretion of these cytokines required adhesion. High levels of fib ronectin, hyaluronic acid, and collagen, all potential ligands for the CD44 adhesion molecule, have been reported in the circulation of IMF patients. However, the Ab-binding capacity of CD44 in IMF monocytes wa s reduced by 50% when compared with normal controls. Our results indic ate that monocytes and adhesion molecules may play a role in the induc tion of fibrogenic cytokines. These parameters may be important to the pathophysiology of BM fibrosis.