STAT3 and ERK Signaling Pathways Are Implicated in the Invasion Activity by Oncostatin M through Induction of Matrix Metalloproteinases 2 and 9

PurposeOur previous studies have shown that oncostatin M (OSM) promotes trophoblast invasion activity through increased enzyme activity of matrix metalloproteinase (MMP)-2 and -9. We further investigated OSM-induced intracellular signaling mechanisms associated with these events in the immortalized human trophoblast cell line HTR8/SVneo.ResultsOSM-induced MMP-2 and -9 protein expression was significantly suppressed by STAT3 inhibition with stattic and STAT3 siRNA silencing, whereas the ERK1/2 inhibitor (U0126) and ERK silencing significantly suppressed OSM-induced MMP-2 protein expression. OSM-induced MMP-2 and MMP-9 enzymatic activities were significantly decreased by stattic pretreatment. The increased invasion activity induced by OSM was significantly suppressed by STAT3 and ERK1/2 inhibition, though to a greater extent by STAT3 inhibition.ConclusionBoth STAT3 and ERK signaling pathways are involved in OSM-induced invasion activity of HTR8/SVneo cells. Activation of STAT3 appears to be critical for the OSM-mediated increase in invasiveness of HTR8/SVneo cells.     

Oncostatin M production by blood and alveolar neutrophils during acute lung injury

Polymorphonuclear neutrophils (PMN) are involved in the pathogenesis of acute lung injury (ALI), secreting numerous mediators such as proteases, reactive oxygen species, and cytokines. Because we had recently observed the ability of normal human PMN to degranulate and synthesize oncostatin M (OSM), an IL-6-family cytokine, we quantified OSM production ex vivo by highly purified blood and alveolar PMN from 24 ventilated patients with ALI, including some patients with severe pneumonia. Most of the patients had no detectable OSM in plasma, and OSM production by cultured blood PMN was similar to that of healthy controls. However, OSM was present in bronchoalveolar lavage (BAL) fluid supernatant, with significantly higher levels during pneumonia. In addition, alveolar OSM levels correlated with the number of PMN obtained by BAL, suggesting that PMN are an important source of OSM within the alveoli. Indeed, purified alveolar PMN from all of the patients, especially those with pneumonia, strongly produced OSM. Interestingly, in the latter patients, alveolar PMN always produced more OSM than autologous blood PMN. These results document the functional duality of PMN in ALI by showing the participation of PMN in the modulation of lung inflammation.     

Oncostatin M in the development of the nervous system

Oncostatin M (OSM) is a member of the interleukin-6 family of cytokines. Of these cytokines, OSM is closely related structually, genetically and functionally to leukemia inhibitory factor. However, OSM-specific biological activities have been reported in hematopoiesis and liver development. Recently, we have demonstrated OSM-specific activities in the nervous systems. In the adult central nervous system (CNS), OSM receptor (OSMR) beta was observed in meningeal cells of pia mater, epithelial cells of the choroid plexus and olfactory astrocyte-like glia surrounding the glomeruli of the olfactory bulb. In the CNS of neonatal mice, OSMRbeta was also expressed in the ventral subnucleus of the hypoglossal nucleus, but disappeared at post-natal day (P) 14. In contrast with the CNS, OSMRbeta was strongly expressed in small-sized non-peptidergic neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG). Interestingly, all OSMRbeta-positive neurons in these ganglia also expressed both TRPV1 (a vanilloid receptor) and P2X3 (a purinergic receptor). In OSM-deficient mice, TRPV1/P2X3/OSMRbeta triple-positive neurons were significantly decreased. Consistent with such histological findings, OSM-deficient mice exhibited a reduction in responses to various stimuli, including mechanical and thermal stimuli. These findings suggest an important role for OSM in the development of a subset of nociceptive neurons.     

细胞老化相关信号途径

细胞老化是正常细胞在受到各种类型的压力刺激后引发的一种程序性反应,表现为永久性细胞周期停滞。细胞老化可能促进生物衰老,并且与肿瘤发生受抑密切相关。至今已知的细胞老化相关信号途径主要有两条,分别是:p53-p21-pRb途径和p16-pRb途径。肿瘤抑制物p53和pRb分别是这两条途径的核心,二者突变在介导细胞老化逃逸、肿瘤发生中起着关键作用。     

Comparative Proteomic Analysis Reveals Activation of Mucosal Innate Immune Signaling Pathways during Cholera

Vibrio cholerae O1 is a major cause of acute watery diarrhea in over 50 countries. Evidence suggests that V. cholerae O1 may activate inflammatory pathways, and a recent study of a Bangladeshi population showed that variants in innate immune genes play a role in mediating susceptibility to cholera. We analyzed human proteins present in the small intestine of patients infected with V. cholerae O1 to characterize the host response to this pathogen. We collected duodenal biopsy specimens from patients with acute cholera after stabilization and again 30 days after initial presentation. Peptides extracted from biopsy specimens were sequenced and quantified using label-free mass spectrometry and SEQUEST. Twenty-seven host proteins were differentially abundant between the acute and convalescent stages of infection; the majority of these have known roles in innate defense, cytokine production, and apoptosis. Immunostaining confirmed that two proteins, WARS and S100A8, were more abundant in lamina propria cells during the acute stage of cholera. Analysis of the differentially abundant proteins revealed the activation of key regulators of inflammation by the innate immune system, including Toll-like receptor 4, nuclear factor kappa-light-chain-enhancer of activated B cells, mitogen-activated protein kinases, and caspase-dependent inflammasomes. Interleukin-12β (IL-12β) was a regulator of several proteins that were activated during cholera, and we confirmed that IL-12β was produced by lymphocytes recovered from duodenal biopsy specimens of cholera patients. Our study shows that a broad inflammatory response is generated in the gut early after onset of cholera, which may be critical in the development of long-term mucosal immunity against V. cholerae O1.     

Oncostatin M inhibits decidualization of normal human endometrial stromal cells

It is well known that oncostatin M binds and activates leukemia inhibitory factor-specific receptors while leukemia inhibitory factor cannot bind oncostatin M-specific receptors. In this study, the differential effects of oncostatin M and leukemia inhibitory factor on cell survival and decidualization of normal human endometrial stromal cells were investigated by using 8-Br-cAMP-induced decidualization assay. Oncostatin M did not affect the viable cell numbers or the prolactin release of unstimulated stromal cells. However, oncostatin M dose-dependently suppressed prolactin releases from 8-Br-cAMP-stimulating stromal cells but enhanced their viable cell numbers. Although oncostatin M significantly enhanced viable cell numbers of 8-Br-cAMP-stimulated stromal cells, it did not affect prolactin secretion from 8-Br-cAMP-induced decidualized cells. Leukemia inhibitory factor significantly enhanced viable cell numbers of 8-Br-cAMP-stimulating cells in a dose-dependent manner as did oncostatin M, while leukemia inhibitory factor did not show any significant suppression of PRL secretion from 8-Br-cAMP-stimulating cells. These results indicate that oncostatin M inhibits the 8-Br-cAMP-induced decidualization process via oncostatin M-specific receptors and that oncostatin M and leukemia inhibitory factor enhance cell survival of 8-Br-cAMP-stimulated prolactin-non-secreting stromal cells mainly via leukemia inhibitory factor receptors. Thus, oncostatin M may autoregulate human endometrial stromal cell survival and decidualization in a paracrine manner.     

Signaling Pathways in Cancer and Embryonic Stem Cells

Cancer cells have the ability to divide indefinitely and spread to different parts of the body during metastasis. Embryonic stem cells can self-renew and, through differentiation to somatic cells, provide the building blocks of the human body. Embryonic stem cells offer tremendous opportunities for regenerative medicine and serve as an excellent model system to study early human development. Many of the molecular mechanism underlying tumorigenesis in cancer and self-renewal in stem cells have been elucidated in the past decade. Here we present a systematic analysis of seven major signaling pathways implicated in both cancer and stem cells. We present on overview of the JAK/STAT, Notch, MAPK/ERK, PI3K/AKT, NF-kB, Wnt and TGF-β pathways and analyze their activation status in the context of cancer and stem cells. We focus on their role in stem cell self-renewal and development and identify key molecules, whose aberrant expression has been associated with malignant phenotypes. We conclude by presenting a map of the signaling networks involved in cancer and embryonic stem cells.     

Oncostatin M gene therapy attenuates liver damage induced by dimethylnitrosamine in rats

To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful, as preventive and curative means, for the treatment of patients with liver damage.     

High-Throughput Analysis of Tumor Necrosis Factor Signaling Pathways in Eight Cell Types during Rat Hepatic Regeneration

This study aims to clarify the relevance of tumor necrosis factor (TNFs) signaling pathways and liver regeneration (LR) at the cellular level. Eight liver cell types were isolated using Percoll density gradient centrifugation and immunomagnetic beads methods. Expressions of TNF signaling pathway-involved genes in each cell type after 2/3 hepatectomy (PH) were detected using gene chip. Results show the following: gene TNFα was upregulated in most cell types, especially in Kupffer cells (KC); TNFβ expression was insignificantly changed in eight liver cell types; the majority of genes involved in four TNFα signaling pathways showed increased expression during LR in hepatocytes (HC); TNFα-induced NFκB pathway-involved genes were upregulated preferentially between 2 and 24 h during LR in biliary epithelial cells (BECs); and TNFα-induced apoptotic pathway genes were downregulated preferentially at progressing phase of LR in dendritic cells (DCs). Referring to the above results, TNFα-mediated signaling pathways, in contrast to TNFβ, play the more proactive role in LR, and four TNFα-mediated signaling pathways seem helpful to regulate biological events in HC; BEC proliferation was partly controlled by TNFα-mediated NFκB pathway; and the impaired TNFα-mediated apoptotic pathway in DCs might contribute to the restoration of DC mass after PH. Briefly, the comparative analysis of genomewide expression profiles of TNF signaling pathways between different cell types is helpful in understanding the implication of TNF signaling in LR at the cellular level.     

Innate Immune Signaling Pathways in Animals: Beyond Reductionism

The immune system plays a crucial role in the maintenance of the stability and equilibrium of the internal environment in living organisms. The field of animal innate immunity has been the global focus of immunological research for decades. It is now known that the functions of innate immunity inevitably rely on the action of the molecular machines of the cascades or network of immune signaling pathways. Up to date, many researches on the immune signaling pathways in animals were focused on identifying the component functions or cascade molecules in details, which essentially followed a reductionist paradigm without paying high attention to the integrated features. The main purpose of this article was dedicated to accentuating the shift of this field from a reductionist to a systemic view. First, the former part of this article made efforts to summarize the main aspects of the signaling pathways of animal innate immunity including the web resources, the recapitulation of highlighted pathways, the cross-talks, and the evolutionary considerations, which heavily emphasized the integrated characteristics of the immune signaling pathways. Subsequently, the later part of this article was based on the holistic feature of the immune signaling pathways, mainly dedicated to propose a novel hypothesis. From a whole perspective, the oscillating balance hypothesis was deliberately formulated to characterize the holistic pattern of the signaling transduction network of animal innate immune system, which might help to understand some immunological phenomena through the integral principle of the immune network.     

Wnt与MAPK信号通路在肿瘤发生中的串话

Wnt和MAPK信号通路在生物进化过程中高度保守,参与调控胚胎发育和细胞增殖、分化及凋亡等.Wnt和MAPK信号通路调控失常可导致胚胎发育异常和肿瘤形成.近年来发现这两条信号通路在肿瘤发生发展中存在着大量串话(crosstalk),彼此之间相互调节,共同发挥促癌或抑癌作用,因此,更好地了解两条通路是如何在肿瘤形成中发生交叉对话对于将来肿瘤治疗非常有价值.     

施旺细胞发育及其调控的信号通路

施旺细胞是由神经嵴细胞分化而来的周围神经系统中特有的成髓鞘细胞,它的发育过程分为施旺细胞前体、不成熟施旺细胞、成熟施旺细胞三个阶段。此过程受到很多细胞因子的影响,如轴突的神经调节蛋白、自分泌因子等。这些因子共同调节施旺细胞的分化、增殖、成熟以及迁移。本文阐述了施旺细胞发育、细胞因子的作用及其作用的受体和信号通路,并展望施旺细胞未来的研究方向和临床应用的潜在价值。     

Eliminating Cancer Stem Cells by Targeting Embryonic Signaling Pathways

Dramatic advances have been made in the understanding of cancer over the past decade. Prime among those are better appreciation of the biology of cancer and the development of targeted therapies. Despite these improvements, however, most tumors remain refractory to anti-cancer medications and frequently recur. Cancer Stem Cells (CSCs), which in some cases express markers of pluripotency (e.g., Oct-4), share many of the molecular features of normal stem cells. These cells have been hypothesised to play a role in tumor resistance and relapse. They exhibit dependence on many primitive regulatory pathways and may be best viewed in the context of embryonic signaling pathways. In this article, we review important embryonic signaling cascades and their differential expression in CSCs. We also discuss these pathways as actionable targets for novel therapies in hopes that eliminating cancer stem cells will lead to an improvement in overall survival for patients.