GENERATION OF CD1(-RESISTANT ACID PHOSPHATASE-POSITIVE OSTEOCLAST-LIKE MULTINUCLEATED GIANT-CELLS FROM HUMAN MONOCYTES()RELB(+) DENDRITIC CELLS AND TARTRATE)

We previously showed that granulocyte-macrophage colony-stimulating fa ctor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimula te the differentiation of human monocytes into two phenotypically dist inct types of macrophages. However, in vivo, not only CSF but also man y other cytokines are produced under various conditions. Those cytokin es may modulate the differentiation of monocytes by CSFs. In the prese nt study, we showed that CD14(+) adherent human monocytes can differen tiate into CD1(+)relB(+) dendritic cells (DC) by the combination of GM -CSF plus interleukin-4 (IL-4) and that they differentiate into tartra te-resistant acid phosphatase (TRAP)-positive osteoclast-like multinuc leated giant cells (MGC) by the combination of M-CSF plus IL-4. Howeve r, the monocyte-derived DC were not terminally differentiated cells; t hey could still convert to macrophages in response to M-CSF. Tumor nec rosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, c-f ms mRNA, and aborting the potential to convert to macrophages. In cont rast to IL-4, interferon-gamma (IFN-gamma) had no demonstrable effect on the differentiation of monocytes. Rather, IFN-gamma antagonized the effect of IL-4 and suppressed the DC and MGC formation induced by GM- CSF + IL-4 and M-CSF + IL-4, respectively. Taken together, these resul ts provide a new aspect to our knowledge of monocyte differentiation a nd provide evidence that human monocytes are flexible in their differe ntiation potential and are precursors not only of macrophages but also of CD1(+)relB(+) DC and TRAP-positive MGC. Such a diverse pathway of monocyte differentiation may constitute one of the basic mechanisms of immune regulation. (C) 1996 by The American Society of Hematology.