Highly glycosylated α1-acid glycoprotein is synthesized in myelocytes, stored in secondary granules, and released by activated neutrophils

Abstract

Alpha-1-acid glycoprotein (AGP) is an acute-phase protein produced by hepatocytes and secreted into plasma in response to infection/injury. We recently assessed the transcriptional program of terminal granulocytic differentiation by microarray analysis of bone marrow (BM) populations highly enriched in promyelocytes, myelocytes/metamyelocytes (MYs), and BM neutrophils. These analyses demonstrated a transient, high mRNA expression of genuine secondary/tertiary granule proteins and AGP in MYs. In agreement with this, immunocytochemistry revealed the presence of AGP protein and the secondary granule protein lactoferrin in cells from the MY stage and throughout granulocytic differentiation. Immunoelectron microscopy demonstrated the colocalization of AGP and lactoferrin in secondary granules of neutrophils. This finding was substantiated by the failure to detect AGP and lactoferrin in blood cells from a patient with secondary/tertiary (specific) granule deficiency. In addition, Western blot analysis of subcellular fractions isolated from neutrophils revealed that neutrophil-derived AGP, localized in secondary granules, was abundant and highly glycosylated compared with endocytosed, plasma-derived AGP localized in secretory vesicles. Exocytosis studies further demonstrated a marked release of AGP and lactoferrin by activated neutrophils. Finally, induction of CCAAT/enhancer-binding protein (C/EBP)-epsilon in a myeloid cell line was shown to increase AGP transcript levels, indicating that AGP expression in myeloid cells, like in hepatocytes, is partially regulated by members of the C/EBP family. Overall, these findings define AGP as a genuine secondary granule protein of neutrophils. Hence, neutrophils, which constitute the first line of defense, are likely to serve as the primary local source of AGP at sites of infection or injury.

Cervicovaginal Levels of Lactoferrin, Secretory Leukocyte Protease Inhibitor, and RANTES and the Effects of Coexisting Vaginoses in Human Immunodeficiency Virus (HIV)-Seronegative Women with a High Risk of Heterosexual Acquisition of HIV Infection

“…Further analysis of the association with other measured factors after controlling for behavioral risk demonstrates a strong association with the presence of leukocytes, as well as erythrocytes. Since Lf is a product of leukocytes, this association is expected and consistent with the high level of vaginal leukocytes we have observed in high-risk women, both with and without a specific diagnosis of vaginosis or vaginitis (16,26). However, there was also an association of Lf with bacterial vaginosis, which was independent of vaginal leukocytosis, unlike Trichomonas infection.…”

The Anticancer Activity of the Marine Sponge Aaptos suberitoides to Protein Profile of Fibrosarcoma Mice (Mus musculus)

“…Response to cell damage triggers systemic acute phase reaction which characterized by increasing of plasma protein synthesis in the liver. If injection of benzo(a)pyrene in subcutaneous continuously (5 times) cause cellular damage, it can be presumed that 41 kDa protein was detected in this study are the same proteins as reported by Theilgaard et al [19]. Protein 41 kDa expressed in group which injected benzo(a)pyrene (groups II, III, IV, V and VI).…”

“…Barriers of polymerization protein were presumed to interfere cell proliferation. Theilgaard et al reported that 41 kDa protein (α1-acid glycoprotein) is one of acute phase proteins which produced by hepatocytes cells and secreted into the plasma in response to infection or cell damage [19]. Generally, cell damage is caused by radiation, toxic chemicals, drugs, toxic bacteria, physical damage, etc.…”

Bovine alpha-1 acid glycoprotein can reduce the chemotaxis of bovine monocytes and modulate CD18 expression

“…From a clinical perspective, alpha-1 acid glycoprotein (AGP) acts as a minor APP in humans and domestic animals, since its concentration is increased up to 3-5 fold during inflammation [16,27]. AGP is mainly produced by hepatic cells: extra-hepatic expression has even been reported in other tissues, such as in white blood cells, including cultured human monocytes [25,31], and in resting or activated polymorphonuclear leukocytes, all able to develop an immunological barrier providing a rapid defence against additional damage caused by inflammation [6,27,28,38]. While being one of the most important binding proteins in plasma [17], AGP also features several immunomodulatory functions [16], such as, for example, the stimulation of human monocytes to release pro-and anti-inflammatory cytokines [36], the inhibition of the chemotactic response of human neutrophils challenged with formyl-methionyl-leucyl-phenylalanine (fMLP) [19,41] and the reduction of platelet aggregation [35].…”