Human IL-34 shares a sequence identity of 99.6%, 72% and 71% with chimpanzee, rat, and mouse IL-34, respectively, on the amino acid level. The IL-34 gene is syntenic in the human, chimpanzee, rat, and mouse genomes. IL-34 has no apparent consensus structural domain or motif, and does not share sequence homology with M-CSF; nevertheless, it binds to the CSFR. These two cytokines are not identical in biological activity and signal activation. IL-34 and CSF show an equivalent ability to support cell growth or survival. However, these cytokines have differing ability to induce the production of chemokines (MCP-1 and eotaxin-2) in primary macrophages, the morphological change in TF-1-fms cells, and the migration of J774A.1 cells. The use of monoclonal antibodies against the CSFR suggests a differential domain binding in the receptor to IL-34 and CSF and, as a result, different bioactivities and signal activation kinetics/strength are produced for these cytokines.