Flowchart: Preparation: IL8

Text Box: Il1Text Box: TNFalpha        



Text Box: Il1rCOPD disease                                 

Text Box: Il8Cervical Cancer           




Text Box: Vegf
Text Box: Cxcr2




J Hum Genet. 2006;51(3):196-203. Epub 2006 Jan 21.

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Association of IL8, CXCR2 and TNF-alpha polymorphisms and airway disease.

Matheson MC, Ellis JA, Raven J, Walters EH, Abramson MJ.

Department of Epidemiology and Preventive Medicine, Monash University, Victoria, Australia. mcmat@unimelb.edu.au

Chronic obstructive pulmonary disease (COPD) is a disease characterised by inflammation of the peripheral airways involving many inflammatory cells and mediators. IL8 is an important inflammatory mediator that is responsible for the migration and activation of neutrophils. Cellular activity of IL8 is mediated by the receptor CXCR2, and transcription of IL8 is controlled by the cytokine tumour necrosis factor (TNFalpha). The aim of our study was to investigate the influence of single nucleotide polymorphisms in IL8, CXCR2 and TNF-alpha on lung function and respiratory symptoms in subjects from Melbourne, Australia. A total of 1,232 participants completed a detailed respiratory questionnaire, spirometry and measurement of gas transfer. Genotyping for the IL8 -251 T-->A, CXCR2 +785C-->T and TNF-alpha -308G-->A polymorphisms was performed using the tetra-primer ARMS-PCR method. The TNF-alpha A allele was associated with a reduced FEF(25-75) (P = 0.03). Inheritance of the CXCR2 T allele was associated with significantly higher diffusing capacity (P = 0.03) and FEF(25-75) (P = 0.02). No association with the IL8 -251 polymorphism was found. Our results suggest that TNF-alpha is associated with COPD-related phenotypes and the CXCR2 +785 SNP may be important in protecting against pulmonary inflammation. These genes may be important candidates in the modulation of the inflammatory response in the airways.

PMID: 16429233 [PubMed - in process]

: Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L818-26. Epub 2006 Jan 6.

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Moraxella catarrhalis induces inflammatory response of bronchial epithelial cells via MAPK and NF-{kappa}B activation and histone deacetylase activity reduction.

Slevogt H, Schmeck B, Jonatat C, Zahlten J, Beermann W, van Laak V, Opitz B, Dietel S, N'guessan PD, Hippenstiel S, Suttorp N, Seybold J.

Dept. of Internal Medicine/Infectious Diseases, Charite-Universitatsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. hortense.slevogt@charite.de).

Moraxella catarrhalis is a major cause of infectious exacerbations of chronic obstructive lung disease (COPD) and may also contribute to the pathogenesis of COPD. Little is known about M. catarrhalis-bronchial epithelium interaction. We investigated activation of M. catarrhalis infected bronchial epithelial cells and characterized the signal transduction pathways. Moreover, we tested the hypothesis that the M. catarrhalis-induced cytokine expression is regulated by acetylation of histone residues and controlled by histone deacetylase activity (HDAC). We demonstrated that M. catarrhalis induced a strong time- and dose-dependent inflammatory response in the bronchial epithelial cell line (BEAS-2B), characterized by the release of IL-8 and GM-CSF. For this cytokine liberation activation of the ERK and p38 mitogen-activated protein (MAP) kinases and transcription factor NF-kappaB was required. Furthermore, M. catarrhalis-infected bronchial epithelial cells showed an enhanced acetylation of histone H3 and H4 globally and at the promoter of the il8 gene. Preventing histone deacetylation by the histone deacetylase inhibitor trichostatin A augmented the M. catarrhalis-induced IL-8 response. After exposure to M. catarrhalis, we found a decrease in global histone deacetylase expression and activity. Our findings suggest that M. catarrhalis-induced activation of il8 gene transcription was caused by interference with epigenetic mechanisms regulating il8 gene accessibility. Our findings provide insight into important molecular and cellular mechanisms of M. catarrhalis-induced activation of human bronchial epithelium.

PMID: 16399788 [PubMed - in process]

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The role of interleukin 1 in growth and metastasis of human cancer xenografts.

Elaraj DM, Weinreich DM, Varghese S, Puhlmann M, Hewitt SM, Carroll NM, Feldman ED, Turner EM, Alexander HR.

Authors' Affiliations: Surgical Metabolism Section, Surgery Branch, and Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Background: Interleukin 1 (IL-1) is a pluripotent cytokine that promotes angiogenesis, tumor growth, and metastasis in experimental models; its presence in some human cancers is associated with aggressive tumor biology. The purpose of these studies was to characterize the role of IL-1 in human cancers and determine if inhibition of IL-1 via its receptor antagonist, IL-1Ra, alters tumor growth and metastatic potential.Methods: IL-1 mRNA or protein levels were determined in clinical tumor samples, cancer cell lines, and xenografts using quantitative reverse transcription-PCR or ELISA. Biological activity of tumor-derived IL-1 protein was shown via induction of permeability across endothelial cell monolayers. The effects of recombinant IL-1Ra on tumor lines in culture (cell proliferation and IL-8 secretion) and in xenograft models (tumor growth, metastatic potential, and intratumoral levels of IL-8 and VEGF) were characterized. The effects of IL-1Ra-mediated regression of xenograft growth on angiogenic proteins (IL-8 and VEGF) were evaluated in an IL-1-producing melanoma (SMEL) xenograft model.RESULTS: IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor specimens including non-small-cell lung carcinoma, colorectal adenocarcinoma, and melanoma tumor samples. Constitutive IL-1 mRNA expression was identified in several cancer cell lines; tumor supernatant from these cell lines produced a significant increase in endothelial cell monolayer permeability, a hallmark event in early angiogenesis, in an IL-1-dependent manner. Moreover, systemic recombinant IL-1Ra resulted in significant inhibition of xenograft growth and neovessel density of IL-1-producing, but not non-IL-1-producing, tumor cell lines. Subsequent analysis of SMEL, a melanoma cell line with constitutive IL-1 production, showed that neither exogenous IL-1 nor IL-1Ra altered tumor cell proliferation rates in vitro. Gene expression analyses of IL-1Ra-treated SMEL xenografts showed a >3-fold down-regulation of 100 genes compared with control including a marked down-regulation of IL-8 and VEGF.CONCLUSIONS: These data show that the IL-1 gene is frequently expressed in metastases from patients with several types of human cancers. IL-1Ra inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers.

PMID: 16489061 [PubMed - in process]