CEACAM1 (CD66a) Promotes Human Monocyte Survival via a Phosphatidylinositol 3-Kinase- and AKT-dependent Pathway

Abstract

CEACAM1 (also known as CD66a) is a transmembrane glycoprotein that mediates homophilic intercellular interactions that influence cellular growth, immune cell activation, and tissue morphogenesis. Various studies have suggested a link between CEACAM1 and cellular apoptosis, including a recent demonstration that ERK1/2 signaling is triggered downstream of CEACAM1. In this study, we reveal that CEACAM1-long binding confers survival signals to human peripheral blood mononuclear cells. CEACAM-specific antibodies effectively protected peripheral blood mononuclear cells from apoptosis, with this effect being particularly dramatic for primary monocytes that undergo spontaneous apoptosis during in vitro culture. This protective effect was reiterated when using soluble CEACAM1, which binds to cell-surface CEACAM1 via homophilic interactions. Monocyte survival correlated with a CEACAM1-dependent up-regulation of the cellular inhibitor of apoptosis Bcl-2 and the abrogation of caspase-3 activation. CEACAM1 binding triggered a phosphatidylinositol 3-kinase-dependent activation of the protein kinase Akt without influencing the activity of extracellular signal-related kinase ERK, whereas the phosphatidylinositol 3-kinase-specific inhibitor LY294002 effectively blocked the protective effect of CEACAM1. Together, this work indicates that CEACAM1 confers a phosphatidylinositol 3-kinase-and Akt-dependent survival signal that inhibits mitochondrion-dependent apoptosis of monocytes. By controlling both ERK/MEK and PI3K/Akt pathways, CEACAM1 functions as a key regulator of contact-dependent control of cell survival, differentiation, and growth.The carcinoembryonic antigen-related cell adhesion molecule (CEACAM1; also known as CD66a and the biliary glycoprotein) is a highly abundant and broadly expressed glycoprotein of the immunoglobulin superfamily. It consists of a single Ig variable domain-like amino terminus, from one to three Ig constant domain-like regions, and a single membrane-spanning segment followed by either a short (CEACAM1-S) or long (CEACAM1-L) cytoplasmic domain. The amino-terminal domain facilitates homophilic (CEACAM1-CEACAM1) intercellular binding that influences a broad spectrum of cellular processes related to cellular activation and/or cell cycle progression (reviewed in Ref.

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

“…Considering that CD300e signaling induced cytokine production in monocytes, we investigated its ability to modulate their life span by assaying cells for annexin V binding after 48 h of incubation. Consistent with the previous observations [26][27][28], a high proportion of monocytes underwent apoptosis when cultured with medium alone (85.574.9%) or in the presence of the isotype-matched control mAb MOPC-21 (86.371.5% apoptotic cells), but were protected in the presence of LPS or macrophage CSF (M-CSF; Fig. 6, panels A and B).…”

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

“…Moreover, differently than in both reports, in our study monocytes were cultured with GM-CSF to prevent spontaneous apoptosis (36 ± 13%, n ¼ 5, data not shown). 21 As suggested by previous studies, 12,15 cytokines, such as GM-CSF and IL-4, might increase the sensitivity of monocytes to Bortezomib. Finally, Bortezomib appears to spare other leukocyte subpopulations, such as B and T lymphocytes, suggesting that it may be a selective inhibitor of the function and survival of cells belonging to the monocyte/DC lineage.…”

“…GM-CSF was added to cultures of purified monocytes to prevent spontaneous apoptosis (36 ± 13%, n ¼ 5, data not shown), 21 whereas IL-3 was added to cultures of purified CD34 þ progenitor cells to maintain their viability. 22 Anti-CD3 or PHA were added to cultures of purified T lymphocytes, when indicated, to induce proliferation.…”

Neisserial Outer Membrane Vesicles Bind the Coinhibitory Receptor Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 and Suppress CD4 + T Lymphocyte Function

“…An expression vector encoding the extracellular domains of CEACAM1 fused to the Fc portion of human immunoglobulin G1 (IgG1) was previously described (50). Recombinant CEACAM1-Fc protein was expressed in COS-7 cells following transient transfection using FuGENE6 reagent (Roche Molecular Biochemicals, Indianapolis, IN) according to the manufacturer's specifications.…”