Recent studies have shown that adiponectin, an adipocyte-derived cytokine, acts as a potent inhibitor of inflammatory responses. It has been also demonstrated that bacterial and viral signalings in host cells are triggered via Toll-like receptor (TLR) molecules. Therefore, in the present study, we investigated whether globular adiponectin (gAd) would be able to inhibit TLR-mediated nuclear factor-jB (NF-jB) signaling in mouse macrophages (RAW264). gAd predominantly bound to the AdipoR1 receptor and suppressed TLR-mediated NF-jB signaling. gAd-mediated inhibition of TLR-mediated IjB phosphorylation and NF-jB activation was eliminated by the pretreatment of cycloheximide. Also their inhibitions of gAd were blocked by preincubation of the cells with an antibody against AdipoR1, but not with an antibody against AdipoR2. Taken together, these findings indicate that adiponectin negatively regulates macrophage-like cell response to TLR ligands via an unknown endogenous product(s).
Immun. 55:947-954, 1987), we showed that human gingival fibroblasts spontaneously produce thymocyteactivating factor (FTAF), which stimulates mitogen-induced thymocyte proliferation. In the present study, we examined the effect of Bacteroides gingivalis fimbriae on FTAF production by the cells, because the fimbriae may be involved in attachment of the organism to periodontal tissues. We show here that the fimbriae bind to the cells, which may subsequently lead to the stimulation of FTAF production by the cells.
The intestinal tract contains many commensal bacteria that modulate various physiological host functions. Dysbiosis of commensal bacteria triggers dysfunction of the intestinal epithelial barrier, leading to the induction or aggravation of intestinal inflammation. To elucidate whether microRNA plays a role in commensal microbiome-dependent intestinal epithelial barrier regulation, we compared transcripts in intestinal epithelial cells (IECs) from conventional and germ-free mice and found that commensal bacteria induced the expression of miR-21-5p in IECs. miR-21-5p increased intestinal epithelial permeability and up-regulated ADP ribosylation factor 4 (ARF4), a small GTPase, in the IEC line Caco-2. We also found that ARF4 expression was up-regulated upon suppression of phosphatase and tensin homolog () and programmed cell death 4 (), which are known miR-21-5p targets, by RNAi. Furthermore, ARF4 expression in epithelial cells of the large intestine was higher in conventional mice than in germ-free mice. ARF4 suppression in the IEC line increased the expression of tight junction proteins and decreased intestinal epithelial permeability. These results indicate that commensal microbiome-dependent miR-21-5p expression in IECs regulates intestinal epithelial permeability via ARF4, which may therefore represent a target for preventing or managing dysfunction of the intestinal epithelial barrier.
Hot phenol-water-extracted lipopolysaccharide (LPS) from Bacteroides gingivalis 381 was purified by Sephadex G-100 chromatography with Tris buffer supplemented with sodium deoxycholate and EDTA (B-LPS). In the present study, B-LPS was examined for its ability to induce interleukin 1 (IL-1) production, a mitogenic response, and macrophage activation in LPS high-responder C3H/HeN and low-responder C3H/HeJ mice. A significant increase in IL-1 production was observed in C3H/HeN and C3H/HeJ peritoneal macrophages treated with various doses (1.0 to 50 ,ug/ml) of B-LPS. IL-1 production by C3H/HeN macrophages treated with B-LPS (10 pg/mI) was about seven times greater than that by C3H/HeJ macrophages. However, the IL-1 production induced by B-LPS (10 ,ug/mI) in C3H/HeN macrophages was four times lower compared with that induced by Escherichia coli 0111 B4 LPS. Also, a significant increase in IL-I production was found in human monocytes stimulated with B-LPS. That B-LPS-induced IL-1 exhibits some molecular weight heterogeneity was indicated from Sephadex G-75 gel filtration profiles. A significant, high mitogenic response by whole spleen cells with 1 x 105 to 5 x 104 cells of either mouse strain per well treated with B-LPS (10 to 50 ,ug/ml) was observed. However, the response of C3H/HeJ mice was less than that of the C3H/HeN strain. Also, glucose consumption assays indicated that enhanced macrophage activation occurred in C3H/HeN but not in C3H/HeJ mice treated with B-LPS. In light of recent studies showing that IL-1 stimulates bone resorption in a mouse calvaria system and collagenase production in fibroblasts, we suggest that B-LPS-induced IL-1 may play a significant role in the pathogenesis of adult periodontal disease.
Previous epidemiologic studies have suggested that periodontal disease is closely related to obesity and glucose tolerance. As the level of adiponectin, an adipocyte-derived cytokine, in plasma had been reported to decrease in obese and type 2 diabetes patients, we explored the role of adiponectin in the etiology of periodontitis using the D clone of RAW264, a clone that exhibits highly efficient osteoclast formation, to determine whether adiponectin acts as a regulatory molecule in osteoclast formation stimulated by lipopolysaccharide of periodontopathic bacteria. We observed that adiponectin acted as a potent inhibitor of osteoclast formation stimulated by Toll-like receptor 4 (TLR4) ligand and receptor activator of NF-kappaB ligand (RANKL). Because NF-kappaB is an important transcription factor in osteoclast formation, we examined the effect of adiponectin on its transcriptional activity. A luciferase assay showed that adiponectin was able to inhibit the TLR4-mediated NF-kappaB activity in RAW264 cells. In addition, we observed that the cytokine was actually able to inhibit TLR4-mediated expression of the gene for inducible nitric oxide synthase and production of nitric oxide in the cells. These observations strongly suggest that adiponectin may function as a negative regulator of lipopolysaccharide/RANKL-mediated osteoclast formation in periodontal disease.
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