Human Plasma Membrane-Derived Vesicles Halt Proliferation and Induce Differentiation of THP-1 Acute Monocytic Leukemia Cells

Abstract

Plasma membrane-derived vesicles (PMVs) are small intact vesicles released from the cell surface that play a role in intercellular communication. We have examined the role of PMVs in the terminal differentiation of monocytes. The myeloid-differentiating agents all-trans retinoic acid/PMA and histamine, the inflammatory mediator that inhibits promonocyte proliferation, induced an intracellular Ca2+-mediated PMV (as opposed to exosome) release from THP-1 promonocytes. These PMVs cause THP-1 cells to enter G0–G1 cell cycle arrest and induce terminal monocyte-to-macrophage differentiation. Use of the TGF-β receptor antagonist SB-431542 and anti–TGF-β1 Ab showed that this was due to TGF-β1 carried on PMVs. Although TGF-β1 levels have been shown to increase in cell culture supernatants during macrophage differentiation and dendritic cell maturation, the presence of TGF-β1 in PMVs is yet to be reported. In this study, to our knowledge we show for the first time that TGF-β1 is carried on the surface of PMVs, and we confirm the presence within PMVs of certain leaderless proteins, with reported roles in myeloid cell differentiation. Our in vitro findings support a model in which TGF-β1–bearing PMVs, released from promonocytic leukemia cells (THP-1) or primary peripheral blood monocytes on exposure to sublytic complement or after treatment with a differentiation therapy agent, such as all-trans retinoic acid, significantly reduce proliferation of THP-1 cells. Such PMVs also induce the terminal differentiation of primary peripheral blood monocytes as well as THP-1 monocytes.

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…50 After treatment with phorbol esters, THP1 cells differentiate into macrophage-like cells, which mimic native monocyte-derived Mws in several respects. 49,51 Because of these characteristics, the THP-1 cell line was broadly proposed as a valuable model for studying the regulation of Mw-specific genes, 51 the mechanisms involved in Mw differentiation 48 and the molecular mechanisms in monocytes and Mws that are associated with the physiology and pathophysiology of inflammatory responses. 50 In this study, green fluorescent protein (GFP)-expressing-THP1 cells were cultured for 18 h in 50 nM phorbol 12-myristate 13-acetate to induce monocyte-to-Mw differentiation.…”

“…The THP1 cell line is one of the most widely used cell lines for investigations of the function and differentiation of monocytes and Mws in response to various inflammatory mediators, such as IFN-c and bacterial LPS. [48][49][50] Undifferentiated THP1 cells resemble primary monocytes/Mws isolated from healthy donors or donors with inflammatory diseases, such as diabetes mellitus and atherosclerosis. 50 After treatment with phorbol esters, THP1 cells differentiate into macrophage-like cells, which mimic native monocyte-derived Mws in several respects.…”

Exosomes derived from bone marrow stromal cells decrease the sensitivity of leukemic cells to etoposide

“…These studies have demonstrated the functions of exosomes in cell apoptosis (14), cell proliferation (15,16), differentiation (15), angiogenesis (17,18), natural killer cell cytotoxicity (19) and induction of antitumor T-cell immunity (20). However, the role of exosomes in the pathogenesis and progression of leukemia has not yet been thoroughly evaluated.…”

Plasma Membrane-derived Vesicles (PMVs) in G6PD Deficient Patients

“…Based on Pantaleo's illustration, the higher levels of PMVs recorded in the G6PD full defect samples can be said to be as a result of increased activated red blood cells in the full defect subjects. This implies that the level of PMVs in a G6PD deficient individual can be used as a marker of the level of severity of erythrocyte stress and therefore crisis [13,14]. There were some limitations during the research work.…”