Monocyte-derived multinucleated giant cells and sarcoidosis

Abstract

Multinucleated giant cells (MGC) are characteristic cells in granulomatous disorders such as sarcoidosis and also formed in vitro from peripheral blood mononuclear cells by stimulation with cytokines, including interferon-γ (IFN-γ), interleukin-3 (IL-3), IL-4, IL-13, and granulocyte-macrophage-colony stimulating factor. In addition to such inflammatory mediators, a factor derived from the pathogens of granulomatous disorders may be necessary for MGC formation. Muramyl dipeptide (MDP), a peptidoglycan portion of bacterial cell walls present in sarcoidal lesions, is one of the candidates and can preferentially induce Langhans-type cells (LGC) in in vitro MGC formation system. Although the exact mechanisms of in vitro MGC formation remains unknown, receptors such as P2X 7, integrins, CD98, and macrophage fusion protein are considered to be involved in cell-to-cell adhesion and subsequent fusion process. Monocytes from sarcoidosis patients expressed higher levels of P2X 7 and had a higher ability to induce MGC than those from healthy controls. Attributable cells for the formation were CD14 ++CD16 − monocytes. Therefore, CD14 ++CD16 − monocytes may infiltrate into sarcoidal lesions and be fused to form LGC by inflammatory mediators and MDP derived from the pathogens of the disorder. Effective agents for sarcoidosis such as tranilast, allopurinol, and captopril inhibited in vitro MGC formation through inhibiting the expression of adhesion molecule and purinergic receptor. Thus, an in vitro MGC formation model would be a useful tool to understand the relevance of MGC in granulomatous disorders.