There are divergent reports in the literature on the character of transglutaminases in monocytes and macrophages. The aim of the present study was to further elucidate the characteristics and functions of various transglutaminases in monocytes and macrophages. Peripheral human blood monocytes were plated and cultured for up to a month and examined for transglutaminase. Freshly prepared monocytes contained cellular Factor XIII only. Successively during culturing, the monocytes matured into macrophages. Cellular Factor XIII correspondingly disappeared and tissue transglutaminase increased during the same time. After approximately 2 weeks in culture only tissue transglutaminase was detected and this remained for the rest of the culturing period. The tissue transglutaminase content was induced by addition of 2 mumols/l retinoic acid. Addition of retinoic acid was not critical for transglutaminase differentiation. Transglutaminase could be associated with phagocytosis of 125I-trypsin-alpha 2-macroglobulin complexes. The phagocytotic capacity of monocytes was approximately 1/4 compared to macrophages cultured for 14 days. Phagocytosis was measured as cellular complex degradation to monoiodo-tyrosine, released to the culture medium. The monocytes and macrophages were incubated at 4 degrees C and 37 degrees C, with and without addition of the transglutaminase inhibitor monodansylthiacadaverine. Addition of 100 mumols/l monodansylthia-cadaverine caused approximately 2/3 inhibition of phagocytosis. These results suggest that transglutaminase differentiates from cellular Factor XIII into tissue type transglutaminase during maturation of monocytes into macrophages and that the differentiation is associated with transglutaminase-dependent phagocytosis.