BackgroundThis study investigated the clinical value of interleukin-6 (IL-6), pentraxin 3 (PTX3), and procalcitonin (PCT) in patients with sepsis and septic shock diagnosed according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).MethodsSerum levels of IL-6, PTX3, and PCT were measured in 142 enrolled subjects (51 with sepsis, 46 with septic shock, and 45 as controls). Follow-up IL-6 and PTX3 levels were measured in patients with initial septic shock within 24 h of hospital discharge. Optimal cut-off values were determined for sepsis and septic shock, and prognostic values were evaluated.ResultsSerum IL-6 levels could discriminate sepsis (area under the curve [AUC], 0.83–0.94, P <  0.001; cut-off value, 52.60 pg/mL, 80.4% sensitivity, 88.9% specificity) from controls and could distinguish septic shock (AUC, 0.71–0.89; cut-off value, 348.92 pg/mL, 76.1% sensitivity, 78.4% specificity) from sepsis. Twenty-eight-day mortality was significantly higher in the group with high IL-6 (≥ 348.92 pg/mL) than in the group with low IL-6 (< 348.92 pg/mL) (P = 0.008). IL-6 was an independent risk factor for 28-day mortality among overall patients (hazard ratio, 1.0004; 95% confidence interval, 1.0003–1.0005; p = 0.024). In septic shock patients, both the initial and follow-up PTX3 levels were consistently significantly higher in patients who died than in those who recovered (initial p = 0.004; follow-up P <  0.001).ConclusionsThe diagnostic and prognostic value of IL-6 was superior to those of PTX3 and PCT for sepsis and septic shock.

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IntroductionTumor-associated macrophages, which are derived from the infiltration of circulating bone marrow-derived monocytes, consist primarily of a polarized M2 macrophage (M2-Mϕ) population and are associated with poor prognosis in various cancers. In the present study, we attempted to assess whether M2-Mϕs derived from bone marrow stimulate the promotion and progression of mammary tumors.Methods4T1 murine mammary carcinoma cells were injected either alone or coupled with M2-Mϕs into the mammary fat pads of syngeneic female Balb/C mice. M2-Mϕs were prepared by treating monocytes isolated from female Balb/C mouse bone marrow with IL-4. Tumor cell growth was determined using an in vivo imaging system and the expression of cell proliferation-related, angiogenesis-related, and lymphangiogenesis-related proteins in tumor tissues was immunohistochemically analyzed. To evaluate the effects of the crosstalk between 4T1 cells and M2-Mϕs on the secretion and mRNA expression of cytokines and the migration of monocytes, 4T1 cells and M2-Mϕs were co-cultured and cytokine antibody array, real-time RT-PCR, and trans-well migration assays were conducted.ResultsThe co-injection of M2-Mϕs into the mammary fat pads of mice increased solid tumor growth and lung metastasis of 4T1 cells as well as the infiltration of CD45+ leukocytes into tumor tissues. The proportions of Ki-67+ proliferating cells and the expression of hypoxia inducible factor-1α, vascular endothelial cell growth factor A, CD31, vascular endothelial cell growth factor C, and lymphatic vessel endothelial receptor-1 were increased significantly in the tumor tissues of mice co-injected with 4T1 cells and M2-Mϕs. The in vitro results revealed that the proliferation of 4T1 cells, the migration of monocytes, and the secretion of granulocyte colony-stimulating factor, IFNγ, IL-1α, IL-2, IL-16, IFNγ-induced protein-10, keratinocyte-derived chemokine, macrophage colony-stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and RANTES were increased when 4T1 cells were co-cultured with M2-Mϕs, as compared with when the 4T1 cells were cultured alone.ConclusionThe crosstalk between 4T1 cells and M2-Mϕs increased the production of cytokines, which may have induced immune cell infiltration into tumor tissues, tumor cell proliferation, angiogenesis, and lymph angiogenesis, thereby increasing solid tumor growth and lung metastasis.

3,3'-Diindolylmethane (DIM), a major acid-condensation product of indole-3-carbinol, has been shown to have multiple anticancer effects in experimental models. Because recurrent or chronic inflammation has been implicated in the development of a variety of human cancers, this study examined the antiinflammatory effects of DIM and the underlying mechanisms using lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. DIM significantly decreased the release of nitric oxide (NO), prostaglandin (PG)E2, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1beta by RAW264.7 cells treated with LPS. DIM inhibited LPS-induced increases in protein levels of inducible NO synthase (iNOS), which were accompanied by decreased iNOS mRNA levels and transcriptional activity. The mRNA levels of phospholipase A2 decreased, whereas neither cyclooxygenases-2 protein nor transcript was altered by DIM. In addition, DIM suppressed LPS-induced nuclear factor-kappaB (NF-kappaB) transcriptional activity, NF-kappaB DNA-binding activity, translocation of p65 (RelA) to the nucleus, and degradation of inhibitor of kappaB alpha. Furthermore, DIM decreased LPS-induced transcriptional activity of activator protein (AP)-1, AP-1 DNA-binding activity, and phosphorylation of stress-activated protein kinase/Jun-N-terminal kinase and c-Jun. We demonstrate that DIM inhibits LPS-induced release of proinflammatory mediators in murine macrophages. Downregulation of NF-kappaB and AP-1 signaling may be one of the mechanisms by which DIM inhibits inflammatory responses.