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.