Journal of cellular physiology
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Malignant mesothelioma is an aggressive tumor of serosal surfaces, which is refractory to current treatment options. Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia, and also to inhibit proliferation of several solid tumors including hepatoma, esophageal, and gastric cancer in vitro. Here we found that As2O3 inhibited cell viability of a mesothelioma cell line, NCI-H2052. ⋯ Moreover, JNK1 siRNA, but not JNK2 siRNA, abrogated As2O3-induced ERK1/2 phosphorylation. JNK2 siRNA together with PD98059, a specific MAPK/ERK kinase inhibitor, suppressed As2O3-induced apoptosis more significantly than JNK2 siRNA alone. These results indicated that As2O3 induces apoptosis of NCI-H2052 cells mainly through JNK1/2 activation, and that ERK1/2 is involved in As2O3-induced apoptosis when JNK1/2 are inactivated.
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Beta-arrestins are scaffolding proteins implicated as negative regulators of TLR4 signaling in macrophages and fibroblasts. Unexpectedly, we found that beta-arrestin-1 (beta-arr-1) and -2 knockout (KO) mice are protected from TLR4-mediated endotoxic shock and lethality. To identify the potential mechanisms involved, we examined the plasma levels of inflammatory cytokines/chemokines in the wild-type (WT) and beta-arr-1 and -2 KO mice after lipopolysaccharide (LPS, a TLR4 ligand) injection. ⋯ Our studies further indicate that regulation of cytokine production by beta-arrestins is likely independent of MAPK and IkappaBalpha-NFkappaB pathways. Our results, however, suggest that LPS-induced chromatin modification is dependent on beta-arrestin levels and may be the underlying mechanistic basis for regulation of cytokine levels by beta-arrestins in vivo. Taken together, these results indicate that beta-arr-1 and -2 mediate LPS-induced cytokine secretion in a cell-type specific manner and that both beta-arrestins have overlapping but non-redundant roles in regulating inflammatory cytokine production and endotoxic shock in mice.
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Interleukin (IL)-27 is a member of IL-6/IL-12 family cytokines produced by antigen-presenting cells in immune responses. IL-27 can drive the commitment of naive T cells to a T helper type 1 (Th1) phenotype and inhibit inflammation in later phases of infection. Human bronchial epithelial cells have been shown to express IL-27 receptor complex. ⋯ These synergistic effects on the up-regulation of ICAM-1 and IL-6 were partially due to the elevated expression of TNF-alpha receptor (p55TNFR) induced by IL-27. Further investigations showed that the elevation of ICAM-1 and IL-6 in human bronchial epithelial cells stimulated by IL-27 and TNF-alpha was differentially regulated by phosphatidylinositol 3-OH kinase (PI3K)-Akt, p38 mitogen-activated protein kinase, and nuclear factor-kappaB pathways. Our results therefore provide a new insight into the molecular mechanisms involved in airway inflammation.
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Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) uniquely displays broad cancer-specific apoptosis-inducing activity through induction of endoplasmic reticulum (ER) stress. We hypothesize that ceramide, a promoter of apoptosis, might contribute to mda-7/IL-24 induction of apoptosis. Ad.mda-7-infected tumor cells, but not normal cells, showed increased ceramide accumulation. ⋯ Pretreatment of cells with FB1 or ISP-1 abolished the induction of ER stress markers (BiP/GRP78, GADD153 and pospho-eIF2alpha) triggered by Ad.mda-7 infection indicating that ceramide mediates ER stress induction by Ad.mda-7. Additionally, recombinant MDA-7/IL-24 protein induced cancer-specific production of ceramide. These studies define ceramide as a key mediator of an ER stress pathway that may underlie mda-7/IL-24 induction of cancer-specific killing.
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Nonsyndromic cleft lip with or without cleft palate (CLP) is a frequent craniofacial malformation caused by both genetic and environmental factors. Maternal smoking during pregnancy is a known risk factor, due to the teratogenic role of nicotine. To assess and compare the impact of CLP and nicotine, we studied the quantitative expression of genes involved in signaling pathways and extracellular matrix (ECM) metabolism in human normal nicotine-treated (NicN) and CLP fibroblasts compared to normal control (CTRL) cells. ⋯ Interestingly, nicotine treatment regulated gene expressions of CD44 and CLPTM1, two candidate genes for CLP. Our findings show a positive association between nicotine treatment and CLP phenotype. Results suggest that nicotine deranges normal palate development, which might contribute to the development of a CLP malformative phenotype, through the impairment of some important signaling systems and ECM composition.