COPD disease
Cervical
Cancer
J Hum
Genet. 2006;51(3):196-203. Epub 2006 Jan 21. : Am
J Physiol Lung Cell Mol Physiol.
2006 May;290(5):L818-26. Epub
2006 Jan 6.
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The
role of interleukin 1 in growth and metastasis of human cancer xenografts.
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,
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
PMID: 16429233 [PubMed - in process]
Moraxella catarrhalis induces
inflammatory response of bronchial epithelial cells via MAPK and
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,
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]
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,
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]