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 excessive deposits of extracellular matrix (ECM) proteins which include fibronectin (FN), collagen type I and hyaluronic acid (HA). We have previously reported that adhesion to polystyrene over-activates MF monocytes. We now confirm their activation by increased CD25 expression and tyrosine phosphorylation. We hypothesize that ECM protein-adhesion molecule interactions induce overproduction of fibrogenic cytokines in MF monocytes leading to BM fibrosis. In this study we found that FN, collagen 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 CD44 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 produced. Immunoprecipitation of CD44 revealed three proteins at approximately 11 kD in MF monocytes and one in NC. Our results indicated that adhesion is important in overproduction of TGF-beta and IL-1, and that their production is at least partly mediated by adhesion molecule-ECM protein interactions. These results implicate at least one adhesion molecule, CD44, in the pathophysiology of the BM fibrosis.
Rameshwar
P
P
Department of Medicine, UMDNJ-New Jersey Medical School, Newark 07103, USA.
Chang
V T
VT
Gascón
P
P
D000328:Adult; D000368:Aged; D002448:Cell Adhesion / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D005353:Fibronectins / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D055728:Primary Myelofibrosis / Q000276:immunology* / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D005353:Fibronectins; D018960:Hyaluronan Receptors; D007375:Interleukin-1; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D006820:Hyaluronic Acid; D003094:Collagen