Aryl Hydrocarbon Receptor Ligands Indoxyl 3-sulfate and Indole-3-carbinol Inhibit FMS-like Tyrosine Kinase 3 Ligand-induced Bone Marrow-derived plasmacytoid Dendritic Cell Differentiation

Aryl hydrocarbon receptor (AhR) regulates both innate and adaptive immune responses by sensing a variety of small synthetic and natural chemicals, which act as its ligands. AhR, which is expressed in dendritic cells (DCs), regulates the differentiation of DCs. However, effects of AhR on the differentiation of DCs are variable due to the heterogeneity of DCs in cell surface marker expression, anatomical location, and functional responses. The plasmacytoid DCs (pDCs), one of DC subsets, not only induce innate as well as adaptive immune responses by secreting type I interferons and pro-inflammatory cytokines, but also induce IL-10 producing regulatory T cell or anergy or deletion of antigen-specific T cells. We showed here that AhR ligands indoxyl 3-sulfate (I3S) and indole-3-carbinol (I3C) inhibited the development of pDCs derived from bone marrow (BM) precursors induced by FMS-like tyrosine kinase 3 ligand (Flt3L). I3S and I3C downregulated the expression of signal transducer and activator of transcription 3 (STAT3) and E2-2 (Tcf4). In mice orally treated with I3S and I3C, oral tolerance to dinitrofluorobenzene was impaired and the proportion of CD11c⁺B220⁺ cells in mesenteric lymph nodes was reduced. These data demonstrate that AhR negatively regulates the development of pDCs from BM precursors induced by Flt3L, probably via repressing the expression of STAT3.

3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103+ Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5

The intestinal immune system maintains oral tolerance to harmless antigens or nutrients. One mechanism of oral tolerance is mediated by regulatory T cell (Treg)s, of which differentiation is regulated by a subset of dendritic cell (DC)s, primarily CD103+ DCs. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays an important role in regulating immunity. The intestines are exposed to various AhR ligands, including endogenous metabolites and phytochemicals. It was previously reported that AhR activation induced tolerogenic DCs in mice or in cultures of bone marrow-derived DCs. However, given the variety of tolerogenic DCs, which type of tolerogenic DCs is regulated by AhR remains unknown. In this study, we found that AhR ligand 3,3'-diindolylmethane (DIM) inhibited the development of CD103+ DCs from mouse bone marrow cells stimulated with Flt3L and GM-CSF. DIM interfered with phosphorylation of STAT3 and STAT5 inhibiting the expression of genes, including Id2, E2-2, IDO-1, and Aldh1a2, which are associated with DC differentiation and functions. Finally, DIM suppressed the ability of CD103+ DCs to induce Foxp3+ Tregs.

Expression of MAGE-1, -2, and -3 genes in gastric carcinomas and cancer cell lines derived from Korean patients

We investigated the expression of MAGE-1, -2, and -3 genes in tissues of 51 gastric carcinomas from Korean patients and in 11 gastric cancer cell lines established in Korea using reverse transcriptase-polymerase chain reaction along with immunohistochemical analyses and DNA sequencing. Among the 51 gastric carcinomas, MAGE-1, -2, and -3 genes were expressed in 16 (31%), 22 (43%), and 17 (33%), respectively, and 31 (60%) expressed at least one of the three genes. In contrast, none of the three MAGE genes were expressed in normal sites of gastric tissue from each cancer patient. Out of 11 gastric cancer cell lines, MAGE-1, -2, and -3 genes were expressed in two (18%), five (46%), and four (36%), respectively. According to the clinicopathological analysis, the expression of any of the three MAGE genes was not significantly correlated with several clinicopathological factors except histologic types (p= 0.067). Immunohistochemical analyses identified positive staining with monoclonal antibodies 77B and 57B specifically against MAGE-1 and -3 proteins, respectively, in nuclei and cytoplasms of cells in mRNA-positive tumor tissue. These findings suggest the possibility as a target for tumor-specific immunotherapy for Korean patients.

Quantitative Correlation between the Biochemical Markers and The Extent of Metastatic Bone Tumors / 대한암학회지

PURPOSE: We investigated the usefulness of urinary pyridinoline (uPyr) and deoxypyridinoline (uDpyr) and serum osteocalcin as markers of bone metastasis, particularly focussing on quantitative correlation between the degree of bone metastasis and the level of biochemical markers. MATERIALS AND METHODS: By using ELISA method we measured the levels of uPyr, uDpyr, and osteocalcin in 100 cancer patients of whom 58 patients had bone metastasis, 42 had no bone metastasis, and 44 control subjects. RESULTS: There was a significant difference in uPyr level between the patients with bone metastasis and the patients without bone metastasis or control group (mean+/-SD, 70.26+/-43.11 vs 38.93+/-21.48 or 25.13+/-8.81 nM/mM Creatinine, p<0.05). And uDpyr level showed more significant elevation in the patients with bone metastasis than in the patients without bone metastasis and in control group (12.63+/-7.51 vs 6.44+/-3.58 and 4.23+/-1.70 nM/mM Creatinine p<0.05). Osteocalcin level showed no significant difference among groups. We could demonstrate a significant quantitative correlation between the extent of bone metastasis and the amount of uPyr (r=0.7482, p<0.001) or uDpyr (r=0.5992, p<0.001). CONCLUSION: uPyr and uDpyr were significantly increased in metastatic bone tumors and quantitatively correlated well with the extent of bone metastasis. Therefore we can use these two markers as an evidence of bone metastasis. Further studies are recommended to decide the usefulness of these markers in the early detection of bone metastasis and in the assessment of response to antiresorptive treatments.