Hyaluronate-enhanced hematopoiesis: Two different receptors trigger the release of interleukin-1 beta and interlenkin-6 from bone marrow macrophages

The glycosaminoglycan hyaluronate (HA) is part of the extracellular environ ment in bone marrow. We show here that HA activates signal transduction cas cades important for hemopoiesis. In myeloid and lymphoid long-term bone mar row cultures (LTBMC), treatment with hyaluronidase (HA'ase) results in redu ced production of both progenitor and mature cells. Exogeneous HA added to LTBMC had the opposite effect: it enhanced hematopoiesis. The effect of HA is mediated through two different HA receptors on bone marrow macrophage-li ke cells, one of which is CD44 while the other is unknown. HA induces bone marrow macrophages to secrete IL-1 beta (CD44-dependent) and IL-6 (CD44 ind ependent). The two receptors address different signal transduction pathways : CD44 links to a pathway activating p38 protein kinase while the other yet unknown receptor induces Erk activity. There was no difference of the effe ct of HA and HA'ase on hematopoiesis in LTBMC and on cytokine production by macrophages in CD44 deficient mice compared with wild-type mice, indicatin g that the CD44 hyaluronate receptor and its signal transduction can be com pensated for. Our data suggest a regulatory role for the extracellular matr ix component HA in hematopoiesis and show the induction of signal transduct ion by HA receptors. (C) 1999 by The American Society of Hematology.