Effects of interleukin-4 on the formation of macrophages and osteoclast-like cells.
The lymphokine interleukin-4 (IL-4) is an important lymphocyte growth factor, and it also has a modulatory role on hematopoiesis. It was recently reported that IL-4 has an inhibitory effect on bone resorption in vitro, but the underlying mechanisms are not well known. We studied its effects on the formation of osteoclast-like cells in mouse bone marrow cultures and in cocultures of spleen cells and stromal cells. The addition of recombinant mouse IL-4 (0.01-10 ng/ml) induced a marked dose-dependent inhibition on the formation of TRAP-positive multinucleated cells (MNC) in bone marrow cultures. The effect was blocked by anti-IL-4 antibodies and was not related to a decreased production of IL-6. The inhibitory effect required the presence of IL-4 during the second half of the culture period. Time course experiments showed that IL-4 impaired the formation of osteoclast-like cells rather than inducing the disappearance of previously formed cells. This inhibitory effect was associated with increased numbers of esterase-positive cells. Moderately high doses of IL-4 (1-10 ng/ml) also induced the formation of abundant macrophage polykaryons that did not form resorption pits. IL-4 had a similar inhibitory effect on the formation of osteoclast-like cells in cocultures of mouse spleen cells and stromal cells. Our results suggest that IL-4 acts on uncommitted macrophage-osteoclast precursors, inducing a preferential differentiation toward the macrophage lineage and thus decreasing the formation of osteoclast-like cells.