95 research outputs found

    Significant association between high serum CCL5 levels and better diseaseā€free survival of patients with early breast cancer

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    Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C-C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead-based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease-free survival (DFS) of patients with high CCL5 levels (cut-off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10- 0.39; P < .0001). An improved overall survival was observed in patients with high CCL5 levels compared to those with low CCL5 levels (P = .024). On the contrary, high immunohistochemical expression of CCL5 in cancer cells was significantly associated with decreased DFS. As serum CCL5 levels did not correlate with CCL5 expression in cancer cells and the relative expression of mRNA CCL5 was elevated in stromal cells in relation to cancer cells, serum CCL5 might be derived not from cancer cells, but from stromal cells. Expression of CCL5 in serum, but not in cancer cells, might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms. Determination of circulating CCL5 levels could be useful for predicting patient prognosis

    IL-18 ; a cytokine translates a stress into medical science

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    Psychological/physical stresses have been reported to exacerbate auto-immune and inflammatory diseases. To clarify a mechanism by which non-inflammatory stresses disrupt host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via ACTH and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form which was released into plasma. Inhibitors of caspase-1, reactive oxygen species and P38 MAPK prevented stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6was not induced in stressed-IL-18 deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses

    Two Distinct Mechanisms Underlying Ī³Ī“ T Cell-Mediated Regulation of Collagen Type I in Lung Fibroblasts

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    Idiopathic pulmonary fibrosis is a chronic intractable lung disease, leading to怀respiratory failure and death. Although anti-fibrotic agents delay disease progression, they are not considered curative treatments, and alternative modalities have attracted attention. We examined the effect of human Ī³Ī“ T cells on collagen type I in lung fibroblasts. Collagen type I was markedly reduced in a Ī³Ī“ T cell number-dependent manner following treatment with Ī³Ī“ T cells expanded with tetrakis-pivaloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2. Collagen type I levels remained unchanged on addition of Ī³Ī“ T cells to the culture system through a trans-well culture membrane, suggesting that cellā€“cell contact is essential for reducing its levels in lung fibroblasts. Re-stimulating Ī³Ī“ T cells with (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) reduced collagen type I levels without cellā€“cell contact, indicating the existence of HMBPP-induced soluble anti-fibrotic factors in Ī³Ī“ T cells. Adding anti-interferon-Ī³ (IFN-Ī³)-neutralizing mAb restored collagen type I levels, demonstrating that human Ī³Ī“ T cell-derived IFN-Ī³ reduces collagen type I levels. Conversely, interleukin-18 augmented Ī³Ī“ T cell-induced suppression of collagen type I. Therefore, human Ī³Ī“ T cells reduce collagen levels in lung fibroblasts via two distinct mechanisms; adoptive Ī³Ī“ T cell transfer is potentially a new therapeutic candidate
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