3553

IL1B

BACKGROUND: Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFbeta1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid treatment or enhanced by the pro-inflammatory cytokine IL-1beta. METHODS: BEAS-2B and primary normal human bronchial epithelial cells were stimulated with TGFbeta1 and expression of epithelial and mesenchymal markers assessed by quantitative real-time PCR, immunoblotting, immunofluorescence microscopy and zymography. In some cases the epithelial cells were also incubated with corticosteroids or IL-1beta. Results were analyzed using non-parametric statistical tests. RESULTS: Treatment of BEAS-2B or primary human bronchial epithelial cells with TGFbeta1 significantly reduced the expression level of the epithelial adherence junction protein E-cadherin. TGFbeta1 then markedly induced mesenchymal marker proteins such as collagen I, tenascin C, fibronectin and alpha-smooth muscle actin mRNA in a dose dependant manner. The process of mesenchymal transition was accompanied by a morphological change towards a more spindle shaped fibroblast cell type with a more motile and invasive phenotype. Corticosteroid pre-treatment did not significantly alter the TGFbeta1 induced transition but IL-1beta enhanced the transition. CONCLUSION: Our results indicate, that TGFbeta1 can induce mesenchymal transition in the bronchial epithelial cell line and primary cells. Since asthma has been strongly associated with increased expression of TGFbeta1 in the airway, epithelial to mesenchymal transition may contribute to the contractile and fibrotic remodeling process that accompanies chronic asthma.

Cytokines present in the tumor microenvironment can promote the invasiveness and metastatic potential of cancer cells. We therefore investigated the effects of interleukin-1 beta (IL-1B) and transforming growth factor beta-3 (TGFB3) on the non-small cell lung carcinoma (NSCLC) cell line A549. We found that these cytokines synergistically activated matrix metalloproteinase (MMP)-1, MMP-3, and MMP-10 gene expression in these cells through mitogen-activated protein kinase (MAPK)-dependent pathways. Consistent with this, both cytokines stimulated epithelial to mesenchymal transition and MAPK-dependent invasion through Matrigel. These studies identify IL-1B and TGFB3 as pro-invasive factors in NSCLC and potential therapeutic targets for tumor progression.CI - Copyright (c) 2012 Elsevier Ireland Ltd. All rights reserved.

The development and progression of hepatocellular carcinoma (HCC) are dependent on its local microenvironment. Hypoxia and inflammation are two critical factors that shape the HCC microenvironment; however, the interplay between the two factors and the involvement of cancer cells under such conditions remain poorly understood. We found that tumor-associated macrophages, the primary proinflammatory cells within tumors, secreted more interleukin 1beta (IL-1beta) under moderate hypoxic conditions due to increased stability of hypoxia inducible factor 1alpha (HIF-1alpha). Under persistent and severe hypoxia, we found that the necrotic debris of HCC cells induced potent IL-1beta release by tumor-associated macrophages with an M2 phenotype. We further confirmed that the necrotic debris-induced IL-1beta secretion was mediated through Toll-like receptor 4/TIR domain-containing adapter-inducing interferon-beta/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in a similar, but not identical, fashion to lipopolysaccharide-induced inflammation. Using mass spectrometry, we identified a group of proteins with O-linked glycosylation to be responsible for the necrotic debris-induced IL-1beta secretion. Following the increase of IL-1beta in the local microenvironment, the synthesis of HIF-1alpha was up-regulated by IL-1beta in HCC cells through cyclooxygenase-2. The epithelial-mesenchymal transition of HCC cells was enhanced by overexpression of HIF-1alpha. We further showed that IL-1beta promoted HCC metastasis in mouse models and was predictive of poor prognosis in HCC patients. CONCLUSION: Our findings revealed an HIF-1alpha/IL-1beta signaling loop between cancer cells and tumor-associated macrophages in a hypoxic microenvironment, resulting in cancer cell epithelial-mesenchymal transition and metastasis; more importantly, our results suggest a potential role of an anti-inflammatory strategy in HCC treatment. (Hepatology 2018;67:1872-1889).CI - (c) 2017 by the American Association for the Study of Liver diseases.

Despite the phenotype has been established that M2 macrophages promotes the metastasis of ESCC, question still remains as to how the M2 macrophages facilitated metastasis of ESCC cells. To begin with, immunohistochemistry was performed to detect the expression of CD163, one typical surface marker of M2 macrophages in 90 paired ESCC and its normal controls after meta-analyzing the relevant studies regarding M2 macrophages in ESCC, confirming that infiltration of M2 macrophages was significantly linked with lymph node metastasis, T classification, and inferior overall survival of ESCC. To explore the mechanism behind, protein factors secreted by M2 macrophages were identified using antibody microarray. Six different significantly differential protein factors were screened out, including IL-1beta, TIMP1, IL-1alpha, MDC, TGF-beta1, and TGF-beta2. Among which, IL-1beta was picked up as cytokine as interest based on previous reports and its absolute fold. Functional analysis of IL-1beta showed that IL-1beta was able to promote migration and invasion of ESCC cells, enhancing epithelial-mesenchymal transition, and activating NF-kappaB pathway. Our study supports the promoting role of M2 macrophages in metastasis of ESCC cells, enriching the profile of protein factors released from M2 macrophages.CI - (c) 2018 Wiley Periodicals, Inc.

Although melatonin has been shown to exert marked antitumor effects against a variety of cancers, the underlying mechanisms remain to be fully elucidated. It has been hypothesized that the anticancer properties of melatonin are associated with its ability to suppress epithelialtomesenchymal transition (EMT) of cancer cells. In the present study, melatonin effectively suppressed interleukin (IL)1betainduced EMT in human gastric adenocarcinoma (GA) cells. Sequential treatment of GA cells with melatonin after IL1beta challenge markedly reversed the IL1betainduced morphological changes, reduced cell invasion and migration, increased betacatenin and Ecadherin expression, and downregulated fibronectin, vimentin, Snail, matrix metalloproteinase (MMP)2 and MMP9 expression. Moreover, IL1betainduced activation of NFkappaB was attenuated following treatment with melatonin. Knockdown of NFkappaB significantly reduced the IL1betainduced EMT in GA cells. Taken together, these findings indicate that melatonin may act by suppressing EMT and tumor progression by inhibiting NFkappaB activity.