CELLULAR INVESTIGATION AND ANALYSIS OF INDUCTION MECHANISMS OF IN VITRO LANGHANS TYPE-MULTINUCLEATED GIANT CELL FORMATION

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The supernatant of concanavalin A-stimulated human peripheral blood mononuclear cells (conditioned medium) generated multinucleated giant cells (MGC) ; Langhans type-(LGC) and foreign body type-MGC (FGC). MDP (N-acetylmuramyl-L-alanyl-D-isoglutamine), a structural analogue of part of the bacterial peptidoglycan, augmented the frequency of LGC.Adhesion molecules and cytokines such as IFN-γ, GM-CSF and IL-3 were found to play an important role in MGC formation but not in LGC induction. Extracellular matrix was also important for MGC formation, particularly cellular fibronectin for LGC induction. MGC were produced by conditioned medium from CD 14^<++> CD 16 monocytes but not from CD 14^+CD16^+ monocytes or immature dendritic cells induced by GM-CSF and IL-4, and slightly from macrophages induced by M-CSF.Addition of MDP did not generate MGC from CD14^+CD16^+ monocytes or dendritic cells but slightly enhanced LGC formation from macrophages. Fusion index of LGC from CD 14^<++> CD16^+ monocytes were enhanced by MDP as same as that in whole monocytes. Next, we examined MGC formation from monocytes of patients with sarcoidosis. MGC were more highly produced from monocytes of sarcoidosis patients than healthy control subjects. The susceptibility of monocytes cultured in conditioned medium for 24 hrs to Bz-ATP-mediated cytolysis was significantly higher in sarcoidosis patients than normal subjects, suggesting that the ability of monocytes to produce MGC through purinergic receptors was enhanced in sarcoidosis patients. Finally, we examined the in vitro effect of tranilast on the formation of MGC.Tranilast inhibited the formation of both types of MGC dose-dependently. Immuno-histochemical stainings showed that tranilast-treated monocytes had less expression of ICAM-1. These findings suggest that tranilast has an efficacy for cutaneous lesions in some cases of granulomatous disorders partly through a direct effect on monocyte/macrophage-lineage cells.