Muramyl dipeptide and mononuclear cell supernatant induce Langhans‐type cells from human monocytes

Muramyl dipeptide (MDP) in bacterial cell walls reportedly evokes epithelioid cell granulomas. We examined its effects on multinucleated‐giant‐cell (MGC) formation from monocytes. Supernatant of concanavalin A‐stimulated peripheral blood mononuclear cells (conditioned medium) generated MGCs from monocytes. MDP significantly increased the fusion index of Langhans‐type MGCs (LGCs) but did not affect total MGCs. N ‐Acetylmuramyl‐ l ‐alanyl‐ l ‐isoglutamine, an MDP analogue, had no effect on MGC formation. MGCs were produced by conditioned medium from CD14 ++ /CD16 − monocytes. MDP enhanced the LGC fusion index from CD14 ++ /CD16 − monocytes. MGCs were not produced from CD14 + /CD16 + monocytes or immature dendritic cells induced by granulocyte macrophage‐colony stimulating factor (GM‐CSF) and interleukin (IL) 4 and only weakly produced from macrophage (M)‐CSF‐ or GM‐CSF‐induced macrophages. Added MDP did not generate MGCs from CD14 + /CD16 + monocytes or dendritic cells but enhanced LGC formation from macrophages. Because IFN‐γ, IL‐3, and GM‐CSF reportedly are important in LGC induction, we added anti‐IFN‐γ, anti‐IL‐3, or anti‐GM‐CSF monoclonal antibody (mAb) concomitantly to the monocyte culture treated with conditioned medium alone or plus MDP. Anti‐IFN‐γ mAb completely abrogated MGC generation, whereas anti‐GM‐CSF and anti‐IL‐3 mAbs significantly inhibited LGCs. These findings suggest that CD14 ++ /CD16 − monocytes are fused to form LGCs by MDP derived from granulomatous‐disease‐causing pathogens with inflammatory mediators such as IFN‐γ, IL‐3, and GM‐CSF.