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 by bone marrow (BM) fibrosis. The BM contains excessive deposits of extracellular matrix proteins and exhibits neovascularization. The fibrosis is hypothesized to be a reactive phenomenon secondary to a clonal myeloid 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 levels of both cytokines were produced in unstimulated IMF monocytes, compared with background levels produced in normal controls. Most of the TGF-beta produced by IMF monocytes was in its active form. The spontaneous induction of IL-1 alpha, IL-1 beta, and TGF-beta in IMF monocytes parallels an increase in their steady state mRNA. Although high levels of cytoplasmic IL-1 alpha, IL-1 beta, and TGF-beta protein were detected in monocytes that were not subjected to any form of adherence, the secretion of these cytokines required adhesion. High levels of fibronectin, 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 was reduced by 50% when compared with normal controls. Our results indicate that monocytes and adhesion molecules may play a role in the induction of fibrogenic cytokines. These parameters may be important to the pathophysiology of BM fibrosis.