Stimulation of human monocytes by endotoxin-associated protein: inhibition of programmed cell death (apoptosis) and potential significance in adjuvanticity

Abstract

Mononuclear phagocytes are essential for adjuvant activity and polyclonal immunoglobulin synthesis induced by endotoxin-associated protein (EP) from Salmonella spp. To define the mechanisms of EP-mediated immunostimulation, we evaluated monocyte functions central to adjuvanticity following exposure to Salmonella typhimurium EP. In this study, we show that EP promotes the survival of monocytes by blocking programmed cell death (apoptosis), enhancing the production of the immunostimulatory cytokine interleukin-l (IL-1) and stimulating the increased expression of HLA-DR and IL-2 receptors, which are cell membrane proteins that facilitate antigen presentation and IL-2 regulation, respectively. These results indicate that, like lipopolysaccharide, EP is a potent activator of human monocytes and suggest that EP-induced immunostimulation may be mediated, in part, by enhanced monocyte survival, cytokine release, and receptor expression.

Estrogen and Progesterone Modulate Monocyte Cell Cycle Progression and Apoptosis

“…Lipopolysaccharide alone did not induce significant apoptosis at any concentration in any of these monocytic cell lines as assessed by PI detection of hypodiploid cells. These findings are consistent with reports that LPS promotes monocyte survival 15,16 …”

“…Lipopolysaccharide, a component of bacterial cell walls, is a potent activator of monocytes/macrophage and inhibits monocyte apoptosis through a bcl‐2 based mechanism 15,16 induced by CD14 receptor binding. CD14 is expressed relatively weakly in KG‐1α and HL‐60 cells, granulocytes, and immature myeloid cells, 30,31 which provides a possible explanation for the lack of significant LPS‐activation effects on cell cycle phase distribution in KG‐1α and K‐562 stem cell‐like cell lines or HL‐60 pro‐myelocytic like cells (Table I).…”

“…Bcl‐2 is a well‐described cell cycle and apoptosis modulatory protein in myelomonocytic cells 32–35 . Based on the observed cell cycle phenomena described above and the reported effects of LPS on bcl‐2, 15,16 we initially characterized bcl‐2 protein levels in the representative myelomonocytic cell lines. In a representative experiment ( n = 3), Fig.…”

“…Bacterial endotoxin or lipopolysaccharide (LPS) activates monocytes and macrophages, eliciting these pro‐inflammatory responses. LPS not only activates monocytes and provokes release of cytokines but also promotes monocyte survival by blocking apoptosis through bcl‐2‐based mechanisms 13–16 . In previous studies, estrogen and progesterone have been shown to variably suppress myelomonocyte proliferation and modulate differentiation and survival; 17–20 however, few studies have characterized specific cell cycle and apoptotic effects of estrogen or progesterone.…”

Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis.

“…Direct comparison of the cytokine-stimulating activity of LAP and LPS has been reported for three bacterial species. Mangan et al (142) have compared the capacities of LPS and LAP from S. typhimurium to stimulate IL-1 synthesis. Significant amounts of mRNA for IL-1␤ were induced in human monocytes exposed to 1 ng of LAP per ml, and in a comparison with the ability of LAP and LPS to induce these cells to release IL-1, the former was consistently three to four times more active.…”