Foreign body-type multinucleated giant cell formation requires protein kinase C β, δ, and ζ

Abstract

Multinucleated giant cells are a classic cellular feature of chronic inflammation, although the mechanism of macrophage fusion leading to their formation is not well understood. Here, we investigate the participation of protein kinase C (PKC) in the interleukin (IL)-4-induced fusion of human monocyte-derived macrophages and foreign body giant cell (FBGC) formation in vitro. The PKC inhibitors H-7 and calphostin C attenuated macrophage fusion, whereas H-8, which is more selective for PKA and PKG, did not. Macrophage fusion was also prevented by the phospholipase C inhibitor, Et-18-OCH 3 , the PKC isoform inhibitors GO6983 or rottlerin and by peptide inhibitors for PKC (20-28), PKCβ, or PKCζ but not by HBDDE or peptide inhibitors for PKCε or PKA. In cultures of fusing macrophages/FBGC, we detected only PKCα, β, δ, and ζ by immunoprecipitation and immunoblotting, and we also observed strong expression of these isoforms by immunocytochemistry. Our collective results suggest that the γ, ε, η, μ, θ, or ι PKC isoforms are not required in the mechanism of IL-4-induced macrophage fusion; whether PKCα is required is unclear. However, new evidence is provided that FBGC formation is supported by PKCβ, PKCδ, and PKCζ in combined diacylglycerol-dependent (PKCβ and PKCδ) and -independent (PKCζ) signaling pathways.

Inflammation induces multinucleation of Microglia via PKC inhibition of cytokinesis, generating highly phagocytic multinucleated giant cells

“…), and foreign‐body induced multinucleation of macrophages is known to be mediated by PKCs (McNally et al . ). Thus, inflammatory agents might cause multinucleation of microglia via stimulation of PKCs.…”

miRNA let-7e Modulates the Wnt Pathway and Early Nephrogenic Markers in Mouse Embryonic Stem Cell Differentiation

“…The use of the PKCβ inhibitor Gö 6983 that acts avoiding phosphorylation of several PKC isoforms, including PKCβ [29], provoked a decrease in the Wnt pathway components, GSK3β serine phosphorylation and β-catenin, concomitant with an increase in the expression of the differentiation markers, indicating the relationship between PKCβ and Wnt pathway in this process.…”

Macrophage fusion leading to foreign body giant cell formation persists under phagocytic stimulation by microspheres in vitro and in vivo in mouse models

“…Anderson and colleagues showed that macrophage fusion induced by interleukin‐4 (IL‐4) is dependant on activity of the mannose receptor, a classical phagocytic mediator,8 though it should be noted that phagocytosis in macrophages can be mediated by a number of different mechanisms 9, 10. Furthermore, this group has established extensive homology between phagocytosis and fusion in endoplasmic reticulum function,11 response to vitronectin expression,12 and downstream kinase signaling activity 13. Others have shown that FBGC can engulf large foreign bodies in a phagocytic‐like manner14 and that macrophages that have phagocytosed particles are capable of fusion in the context of osteoclastic differentiation 15.…”