No abstract

Differentiated osteoclasts have a short life span. We tested various cytokines and growth factors for the effects on the survival of purified mature osteoclasts. In the absence of any added factors, osteoclasts exhibited the survival rate of less than 25% after a 24-h incubation. Among the tested factors, tumor necrosis factor-␣ (TNF-␣) was found to increase the survival rate to ϳ80%. The TNF-␣-enhanced survival of osteoclasts appeared to be associated with reduction in apoptosis and suppression of caspase activation. The antiapoptotic signaling pathways involved in the TNF-␣-induced osteoclast survival were investigated. TNF-␣ treatment increased the phosphorylation of Akt in osteoclasts, which was suppressed by a phosphatidylinositol 3-kinase inhibitor LY294002 and an Src family kinase-selective inhibitor PP1. These inhibitors also attenuated the TNF-␣ stimulation of osteoclast survival. In addition an increase in the phosphorylation of ERK was observed upon TNF-␣ stimulation. PD98059, a specific inhibitor of the ERKactivating kinase MEK-1, abolished the TNF-␣-induced ERK phosphorylation and osteoclast survival, and in these responses the involvement of Grb2 and ceramide was observed. These results suggest that TNF-␣ promotes the survival of osteoclasts by engaging the phosphatidylinositol 3-kinase Akt and MEK/ERK signaling pathways.Osteoclasts are multinucleated cells responsible for bone resorption, which occurs throughout the life as well as during bone development. These cells are continuously formed from the monocyte/macrophage lineage of hematopoietic cells to replace dying cells. The formation and activation of osteoclasts are regulated by numerous cytokines, hormones, and growth factors. Recently, a tumor necrosis factor (TNF) 1 family molecule, receptor activator of nuclear factor B ligand (RANKL; also called TRANCE, ODF, and OPGL), was found to play essential roles for osteoclast differentiation and activation (1-4). Subsequently, many osteotrophic factors were shown to induce the expression of RANKL on supporting osteoblastic/ stromal cells explaining the necessity of cell-to-cell contact between the supporting cells and osteoclast progenitor cells for differentiation of the latter (1, 5). Binding of RANKL to its receptor RANK, a TNF receptor (TNFR) family protein present on osteoclast lineage and dendritic cells, induces a strong activation of NF-B and c-Jun N-terminal kinase through the membrane-proximal adaptor molecules TNFR-associated factors (TRAFs) (3, 4, 6 -10). The crucial roles of RANK and RANKL were clearly shown in knock-out mice that displayed osteopetrosis that results from the lack of osteoclast formation (11, 12). Once terminally differentiated, osteoclasts have a short life span and undergo apoptotic cell death. Survival of osteoclasts appears to be dependent on osteotrophic factors presented by osteoblast/stromal cells, and in the absence of the supporting cells, osteoclasts readily undergo apoptosis (13). Some studies have also reported that the survival of osteoclasts is regulate...

Background— The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation. Methods and Results— We generated CD137-deficient apolipoprotein E–knockout mice ( ApoE −/− CD137 −/− ) and LDL-receptor–knockout mice ( Ldlr −/− CD137 −/− ) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-γ, monocyte chemoattractant protein-1, and tumor necrosis factor-α. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels. Conclusions— CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.

We investigated whether four common microRNA polymorphisms (miR-146aC>G [rs2910164], miR-149T>C [rs2292832], miR-196a2T>C [rs11614913], and miR-499A>G [rs3746444]) are associated with the susceptibility and prognosis of gastric cancer in the Korean population. The four microRNA single-nucleotide polymorphisms (SNPs) were identified in a case-control study (461 patients; 447 controls) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in the Korean population. When patients were stratified into diffuse and intestinal-type gastric cancer groups, subjects with the miR-499AG and AG + GG genotypes had reduced adjusted odds ratios (AORs) for diffuse-type gastric cancer (AOR = 0.54 with 95% confidence interval [CI] = 0.31-0.97; AOR = 0.57 with 95% CI = 0.33-0.97). In the stratified analyses for gastric cancer risk, the miR-146aGG and CG + GG genotypes were associated with increased risk of gastric cancers among the non-smokers, whereas the miR-149TC and TC + CC genotypes showed lower risk of gastric cancer in males. The miR-196a2CC genotype was associated with elevated gastric cancer risk among females. For gastric cancer prognosis, intestinal-type gastric cancer patients with miR-146aCG + GG genotypes had significantly higher survival rates (log-rank P = 0.030) than patients with the CC genotype, and patients with the miR-499AA genotype had significantly increased survival rates compared to patients with the AG + GG genotypes (log-rank P = 0.013). When miR-146aCG + GG and miR-499AA genotypes were combined, the survival rate of intestinal-type gastric cancer patients was elevated (log-rank P < 0.001). No association was found between gastric or diffuse-type cancer prognosis and other miRNAs. Our data demonstrate that specific miRNA SNPs are associated with gastric cancer susceptibility (miR-499A>G) and prognosis (miR-146aC>G and miR-499A>G) in the Korean population depending on gastric cancer type.

In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.