Immunoregulatory effects of AFP domains on monocyte-derived dendritic cell function

Abstract

BackgroundAlpha-fetoprotein (AFP) is a tumor-associated glycoprotein that functions in regulation of both ontogenic and oncogenic growth. Recent study showed that AFP can induce apoptosis or impair monocyte-derived dendritic cell (MDDC) function. However, it is still unclear which AFP domain (D-AFP) plays major role in this function.ResultsAs expected monocytes cultured in the presence of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin-4 (IL-4) developed into MDDC. Up-regulation of HLA-DR and CD11c as well as loss of CD14 molecules could be observed. Full length AFP (FL-AFP), domain 2 AFP (D2-AFP) and D3-AFP, but not D1-AFP, significantly inhibited the expression of HLA-DRhigh/CD11chigh and CD80+/CD86high molecules. In contrast, CD83 expression was substantially down-regulated in all samples. Expression of CD40 was significantly suppressed by FL-AFP but not by any D-AFPs. Finally, both FL-AFP and D-AFP impaired the MDDC ability to secrete IL-12 (p70).ConclusionsD2- and D3- but not D1-AFP extensively suppresses the MDDC function. All the recombinant AFP proteins impaired the ability of MDDC to secrete IL-12.

Tumor-Derived α-Fetoprotein Impairs the Differentiation and T Cell Stimulatory Activity of Human Dendritic Cells

“…Setiyono et al . report that domains 2 and 3, but not domain 1, of the AFP protein possess immunoregulatory activity (12). Notably, domain 2 contains the major fatty acid-binding site of the protein, providing further evidence of a potential role for fatty acids in tAFP-based DC dysfunction (40).…”

“…An immunoregulatory role for AFP has also been proposed. Early studies revealed an inhibitory effect of cord blood-derived human AFP on lymphocyte function, while more recent reports suggest that AFP exerts its immunosuppressive activity through the induction of DC dysfunction (7–12). There is currently little consensus, however, on which cell subsets and/or signaling pathways are the primary targets of AFP-mediated immunosuppression.…”

Quantitative assessment of cell viability based on flow cytometry and microscopy

“…Viability testing is of high importance in many areas of cell research including cytotoxicity tests based on cell and tissue cultures (1–3), the selection of proper tissue scaffolds for regenerative medicine (4), quality assurance of products for transplantation (5, 6), research for cancer treatment (7, 8), and also for the inspection of hybridoma cells (9–11). For the evaluation of cell viability, flow cytometry and microscopy are used besides the detection of cellular secretion products (11).…”

The effect of alpha fetoprotein on NF-κB translocation in lipopolysaccharide induced monocyte-derived dendritic cell

“…Dysfunction of DC is one of the critical mechanisms to escape immune surveillance. 4 Since our previous report proved that alpha fetoprotein (AFP) inhibited synthesis of interleukin-12 (IL-12) 3 and NF-κB is the transcription factor of IL-12, 5 we assumed that nuclear factor kappa B (NF-κB) was involved in this mechanism. In order to deepen our understanding on intracellular mechanism affected by Alpha fetoprotein (AFP) is a 70 kDa oncofetal protein and is detected both fetally and maternally during pregnancy and then its expression is turned off completely after birth.…”

“…1,2 Our previous study revealed this immunomodulatory properties of AFP might happen through the impairment of monocytes-derived dendritic cell (MDDC) as antigen presenting cell (APC). 3 A majority of hepatocellular carcinoma (HCC) patients AFP, we conducted a study to determine which element in NF-κB signaling pathway that was directly inhibited by AFP. This preliminary report aimed to determine the effect of AFP on nuclear translocation of NF-κB using lipopolysaccharide (LPS) as activator for NF-κB signaling pathway.…”