Dendritic cells (DCs) are able in tissue culture to phagocytose and present antigens derived from infected, malignant, and allogeneic cells. Here we show directly that DCs in situ take up these types of cells after fluorescent labeling with carboxyfluorescein succinimidyl ester (CFSE) and injection into mice. The injected cells include syngeneic splenocytes and tumor cell lines, induced to undergo apoptosis ex vivo by exposure to osmotic shock, and allogeneic B cells killed by NK cells in situ. The CFSE-labeled cells in each case are actively endocytosed by DCs in vivo, but only the CD8+ subset. After uptake, all of the phagocytic CD8+ DCs can form major histocompatibility complex class II–peptide complexes, as detected with a monoclonal antibody specific for these complexes. The CD8+ DCs also selectively present cell-associated antigens to both CD4+ and CD8+ T cells. Similar events take place with cultured DCs; CD8+ DCs again selectively take up and present dying cells. In contrast, both CD8+ and CD8− DCs phagocytose latex particles in culture, and both DC subsets present soluble ovalbumin captured in vivo. Therefore CD8+ DCs are specialized to capture dying cells, and this helps to explain their selective ability to cross present cellular antigens to both CD4+ and CD8+ T cells.

Compared with pioglitazone, ipragliflozin exerts equally beneficial effects on NAFLD and glycemic control during the treatment of patients with type 2 diabetes complicated by NAFLD. Furthermore, ipragliflozin significantly reduced body weight and abdominal fat area.

ObjectiveTo investigate whether preoperative corticosteroid administration plays a role in attenuating postoperative morbidity. Summary Background DataThere is as yet no consensus on the beneficial effects of steroids in alleviating surgical stress. MethodsA total of 66 patients undergoing surgery for thoracic esophageal cancer were randomly categorized preoperatively into two groups of 33 patients each. One group was administered an intravenous infusion of methylprednisolone (10 mg/kg body weight) 30 minutes before the surgery (MP group), while the other group received a placebo infusion (control group). The primary endpoint was organ system failure during the first 7 days after surgery. Comparisons of surgery-related complications, cytokine responses, and blood counts were also made between the two groups. ResultsThe percentage of patients in the MP group who had one or more organ system failures was 33%, significantly lower than the corresponding percentage of 61% in the control group. The surgery-related complication rate and long-term survival rate were similar in the two groups. The peak plasma levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8 were significantly lower in the MP group than in the control group. Changes in the plasma levels of IL-10 were significantly larger in the MP group. No significant differences in the circulating lymphocyte and neutrophil counts were observed between the groups. ConclusionsThe results suggest that prophylactic administration of corticosteroids is associated with a decrease in postoperative morbidity in patients undergoing invasive surgery. The laboratory data suggest that corticosteroids may attenuate surgical stress-induced inflammatory responses both directly by suppressing the release of proinflammatory cytokines and via inducing IL-10 synthesis.

Objective. To clarify the function of osteoclast-like multinuclear cells differentiated from bone marrowderived macrophages (BMMs) by a combination of tumor necrosis factor ␣ (TNF␣) and interleukin-6 (IL-6), and to investigate the molecular mechanisms underlying the differentiation.Methods. BMMs were stimulated by TNF␣ and/or IL-6. The cells were then compared with conventional osteoclasts differentiated in vitro by RANKL. An in vitro pit formation assay on dentine slices and an in vivo resorption assay of calvarial bones were performed. We also evaluated the activities and expression levels of NF-B, c-Fos, and NF-ATc1, which are essential to the differentiation of conventional osteoclasts. Small interfering RNA was used to knock down c-Fos. The effects of genetic ablation of STAT-3 and pharmacologic inhibitors of NF-AT, JAK, and ERK were also studied.Results. Osteoclast-like cell differentiation depended on TNF␣ and IL-6 and was not inhibited by osteoprotegerin. These differentiated cells were associated with both in vitro and in vivo bone resorption activity. TNF␣ and IL-6 had a synergistic effect on the activity and expression of c-Fos. Knockdown of c-Fos inhibited the expression of NF-ATc1 and the differentiation of osteoclast-like cells. All of these inhibitors blocked differentiation of the cells in vitro, but surprisingly, the conditional knockout of STAT-3 did not. Tofacitinib also inhibited the bone destruction caused by TNF␣ and IL-6 in vivo.Conclusion. Our results demonstrate that a combination of the inflammatory cytokines TNF␣ and IL-6 can induce osteoclast-like cells that have in vitro and in vivo bone-resorptive activity.