Inasmuch as we recently demonstrated that IL-4 is a strong inducer of monocyte/macrophage fusion and IL-13 has been observed to mimic many of the biologic effects of IL-4, the ability of IL-13 to promote human macrophage fusion in vitro was tested and compared with IL-4-mediated fusion. IL-13 induced the fusion of monocyte-derived macrophages as potently as IL-4 under identical culture conditions, and resulted in foreign body-type giant cell formation. At optimal concentrations of cytokine added, statistically equal numbers of macrophages participated in IL-13- and IL-4-induced fusion (66.1 +/- 4.6% and 63.9 +/- 4.4%, respectively). However, the effects of IL-13 and IL-4 were not additive or synergistic, and the maximum fusion obtained when both IL-4 and IL-13 were added was 63.8 +/- 3.6%. Only anti-human IL-13 Abs inhibited IL-13-induced foreign body giant cell formation; the fusion-inducing effects of IL-13 continued to be observed in the presence of neutralizing Abs to IL-4 and several other anti-cytokine Abs, including Abs against IFN-gamma, granulocyte-macrophage CSF, IL-3, and TNF-alpha. IL-13 also significantly enhanced the fluorescence intensity detected by anti-human macrophage mannose receptor Abs, indicating that IL-13, like IL-4, up-regulates expression of the receptor that may be an essential participant in macrophage fusion. The results of this study demonstrate that IL-13, like IL-4, is a potent human macrophage fusion factor, and suggest that although IL-13 acts independently of IL-4 to promote foreign body giant cell formation, it may trigger a common mechanism for macrophage fusion.