scholarly journals KIT oncogene inhibition drives intratumoral macrophage M2 polarization

2013 ◽  
Vol 210 (13) ◽  
pp. 2873-2886 ◽  
Author(s):  
Michael J. Cavnar ◽  
Shan Zeng ◽  
Teresa S. Kim ◽  
Eric C. Sorenson ◽  
Lee M. Ocuin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein C ◽  
Cancer Microenvironment ◽  
M2 Polarization ◽  
Enhancer Binding Protein ◽  
Activating Mutation ◽  
Similar Gene Expression Profile ◽  
And Function ◽  
Human Sarcoma ◽  
Similar Gene

Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.

scholarly journals High-throughput transcriptomic analysis of human primary hepatocyte spheroids exposed to per- and polyfluoroalkyl substances (PFAS) as a platform for relative potency characterization

2021 ◽  
Author(s):  
A Rowan-Carroll ◽  
A Reardon ◽  
K Leingartner ◽  
R Gagné ◽  
A Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cholesterol Biosynthesis ◽  
Health Hazard ◽  
Biological Responses ◽  
Similar Gene Expression Profile ◽  
Transcriptional Changes ◽  
Hazard And Risk ◽  
Hepatocyte Spheroids ◽  
Similar Gene ◽  
Identify Gene Expression

Abstract Per- and poly-fluoroalkyl substances (PFAS) are widely found in the environment because of their extensive use and persistence. Although several PFAS are well studied, most lack toxicity data to inform human health hazard and risk assessment. This study focussed on four model PFAS: perfluorooctanoic acid (PFOA; 8 carbon), perfluorobutane sulfonate (PFBS; 4 carbon), perfluorooctane sulfonate (PFOS; 8 carbon), and perfluorodecane sulfonate (PFDS; 10 carbon). Human primary liver cell spheroids (pooled from 10 donors) were exposed to 10 concentrations of each PFAS and analyzed at four time-points. The approach aimed to: (1) identify gene expression changes mediated by the PFAS; (2) identify similarities in biological responses; (3) compare PFAS potency through benchmark concentration analysis; and (4) derive bioactivity exposure ratios (ratio of the concentration at which biological responses occur, relative to daily human exposure). All PFAS induced transcriptional changes in cholesterol biosynthesis and lipid metabolism pathways, and predicted PPARα activation. PFOS exhibited the most transcriptional activity and had a highly similar gene expression profile to PFDS. PFBS induced the least transcriptional changes and the highest benchmark concentration (i.e., was the least potent). The data indicate that these PFAS may have common molecular targets and toxicities, but that PFOS and PFDS are the most similar. The transcriptomic bioactivity exposure ratios derived here for PFOA and PFOS were comparable to those derived using rodent apical endpoints in risk assessments. These data provide a baseline level of toxicity for comparison with other known PFAS using this testing strategy.

scholarly journals Cultured Human Adipose Tissue Pericytes and Mesenchymal Stromal Cells Display a Very Similar Gene Expression Profile

2015 ◽  
Vol 24 (23) ◽  
pp. 2822-2840 ◽  
Author(s):  
Lindolfo da Silva Meirelles ◽  
Tathiane Maistro Malta ◽  
Virgínia Mara de Deus Wagatsuma ◽  
Patrícia Viana Bonini Palma ◽  
Amélia Goes Araújo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Gene Expression Profile ◽  
Mesenchymal Stromal Cells ◽  
Expression Profile ◽  
Stromal Cells ◽  
Human Adipose Tissue ◽  
Similar Gene Expression Profile ◽  
Similar Gene

scholarly journals Neonatal and Adult CD4+CD3− Cells Share Similar Gene Expression Profile, and Neonatal Cells Up-Regulate OX40 Ligand in Response to TL1A (TNFSF15)

2006 ◽  
Vol 177 (5) ◽  
pp. 3074-3081 ◽  
Author(s):  
Mi-Yeon Kim ◽  
Kai-Michael Toellner ◽  
Andrea White ◽  
Fiona M. McConnell ◽  
Fabrina M. C. Gaspal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Ox40 Ligand ◽  
Similar Gene Expression Profile ◽  
Similar Gene

scholarly journals Identification of myeloid cells in the human enthesis as the main source of local IL-23 production

2019 ◽  
Vol 78 (7) ◽  
pp. 929-933 ◽  
Author(s):  
Charlie Bridgewood ◽  
Abdulla Watad ◽  
Tobias Russell ◽  
Timothy M Palmer ◽  
Helena Marzo-Ortega ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Cell Population ◽  
Expression Profile ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Ccr2 Gene ◽  
Similar Gene Expression Profile ◽  
Normal Human ◽  
Similar Gene

ObjectiveWe investigated whether the normal human spinal enthesis contained resident myeloid cell populations, capable of producing pivotal proinflammatory cytokines including tumour necrosis factor (TNF) and interleukin (IL)-23 and determined whether these could be modified by PDE4 inhibition.MethodsNormal human enthesis soft tissue (ST) and adjacent perientheseal bone (PEB) (n=15) were evaluated using immunohistochemistry (IHC), digested for myeloid cell phenotyping, sorted and stimulated with different adjuvants (lipopolysaccharide and mannan). Stimulated enthesis fractions were analysed for inducible production of spondyloarthropathy disease-relevant mediators (IL-23 full protein, TNF, IL-1β and CCL20). Myeloid populations were also compared with matched blood populations for further mRNA analysis and the effect of PDE4 inhibition was assessed.ResultsA myeloid cell population (CD45+ HLADR+ CD14+ CD11c+) phenotype was isolated from both the ST and adjacent PEB and termed ‘CD14+ myeloid cells’ with tissue localisation confirmed by CD14+ IHC. The CD14− fraction contained a CD123+ HLADR+ CD11c− cell population (plasmacytoid dendritic cells). The CD14+ population was the dominant entheseal producer of IL-23, IL-1β, TNF and CCL20. IL-23 and TNF from the CD14+ population could be downregulated by a PDE4I and other agents (histamine and 8-Bromo-cAMP) which elevate cAMP. Entheseal CD14+ cells had a broadly similar gene expression profile to the corresponding CD14+ population from matched blood but showed significantly lower CCR2 gene expression.ConclusionsThe human enthesis contains a CD14+ myeloid population that produces most of the inducible IL-23, IL-1β, TNF and CCL20. This population has similar gene expression profile to the matched blood CD14+ population.

Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile

2005 ◽  
Vol 36 (4) ◽  
pp. 341-347 ◽  
Author(s):  
Rajesh Kannangai ◽  
Anna Mae Diehl ◽  
Jason Sicklick ◽  
Marcus Rojkind ◽  
David Thomas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Hepatic Angiomyolipoma ◽  
Similar Gene Expression Profile ◽  
Similar Gene

scholarly journals High-throughput transcriptomic evaluation of per- and polyfluoroalkyl substances (PFAS) in primary human liver spheroids to inform read-across

2020 ◽  
Author(s):  
A. Rowan-Carroll ◽  
A. Reardon ◽  
K. Leingartner ◽  
R. Gagné ◽  
A. Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Assessment ◽  
Cholesterol Biosynthesis ◽  
Health Hazard ◽  
Biological Response ◽  
Biological Responses ◽  
Similar Gene Expression Profile ◽  
Transcriptional Changes ◽  
Hazard And Risk ◽  
Similar Gene

AbstractPer- and poly-fluoroalkyl substances (PFAS) are widely found in the environment because of their extensive use and persistence. Although a few PFAS are well studied, most lack toxicity data to inform human health hazard and risk assessment. This study focussed on four model PFAS: perfluorooctanoic acid (PFOA; 8 carbon), perfluorobutane sulfonate (PFBS; 4 carbon), perfluorooctane sulfonate (PFOS; 8 carbon), and perfluorodecane sulfonate (PFDS; 10 carbon). Human primary liver cell spheroids (i.e., pooled-donor) were exposed to 10 concentrations of PFAS over four time-points. The approach aimed to: (1) identify the extent to which the PFAS modulated gene expression; (2) identify similarities in biological responses; (3) compare PFAS potency through benchmark concentration (BMC) analysis; and (4) derive bioactivity exposure ratios (BERs: ratio of concentration at which biological response occurs converted to administered equivalent dose relative to human daily exposure). All PFAS induced transcriptional changes of cholesterol biosynthesis and lipid metabolism, and appeared to activate PPARα. PFOS exhibited the most transcriptional perturbations and had a highly similar gene expression profile to PFDS. PFBS induced the least transcriptional changes and had the highest BMCs. The data indicate that these four chemicals may have common molecular targets and toxicities, but that PFOS and PFDS are the most similar. BERs derived for PFOA and PFOS had relatively low margins; the transcriptomic BER was slightly more conservative than BERs derived from rodent apical endpoints used as points of departure in risk assessment. The data provide a baseline on which to compare the toxicity of other PFAS using this testing strategy.

Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture

1992 ◽  
Vol 12 (6) ◽  
pp. 2553-2560
Author(s):  
D Mischoulon ◽  
B Rana ◽  
N L Bucher ◽  
S R Farmer
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Protein C ◽  
Binding Protein ◽  
Regenerating Liver ◽  
Differentiated Cells ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Alpha Gene ◽  
Rat Tail

As an approach to understanding physiological mechanisms that control the proliferation of highly differentiated cells, we are addressing whether certain hepatic transcription factors participate in mechanisms that control the growth of hepatocytes. We have focused on CCAAT enhancer-binding protein (C/EBP alpha), a transcription factor which is highly abundant in normal liver and is considered to regulate expression of many genes, including some involved in energy metabolism (S. L. McKnight, M. D. Lane, and S. Gluecksohn-Walsh. Genes Dev. 3:2021-2024, 1989). Using Northern (RNA) blot analysis, we have examined the expression of C/EBP alpha mRNA during liver regeneration and in primary cultures of hepatocytes. C/EBP alpha mRNA levels decrease 60 to 80% within 1 to 3 h after partial hepatectomy as the cells move from G0 to G1 and decrease further when cells progress into S phase. Run-on transcription analysis is in agreement with the Northern blot data, thus suggesting that C/EBP alpha is transcriptionally regulated in regenerating liver. C/EBP alpha mRNA expression also decreases dramatically during the growth of freshly isolated normal hepatocytes cultured under conventional conditions (on dried rat tail collagen; stimulated to proliferate by epidermal growth factor [EGF] and insulin). Cultures of hepatocytes on rat tail collagen in the presence or absence of EGF clearly show that within 3 h, EGF depresses C/EBP alpha mRNA expression and that this effect is substantially greater by 4 h. Inhibition of protein synthesis in the liver by cycloheximide or in cultured hepatocytes by puromycin or cycloheximide effectively blocks the down-regulation of C/EBP alpha gene expression, apparently by stabilizing the normal rapid turnover of the C/EBP alpha mRNA (half-life of <2 h). This drop in C/EBP alpha gene expression in response to activation of hepatocyte growth is consistent with the proposal that C/EBP alpha has an antiproliferative role to play in highly differentiated cells (R. M. Umek, A. D. Friedman, and S. L. McKnight, Science 251: 288-292, 1991).

Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-κB and C/EBP-mediated mechanism

2005 ◽  
Vol 288 (5) ◽  
pp. C1125-C1133 ◽  
Author(s):  
Kenneth J. Serio ◽  
K. Veera Reddy ◽  
Timothy D. Bigby
Keyword(s):  
Gene Expression ◽  
Chromatin Immunoprecipitation ◽  
Protein C ◽  
Protein Gene ◽  
Prolonged Exposure ◽  
Human Monocyte ◽  
Dominant Negative ◽  
Mononuclear Phagocytes ◽  
Nuclear Extracts ◽  
Enhancer Binding Protein

We examined induced expression of the 5-lipoxygenase-activating protein (FLAP), which is critical for leukotriene synthesis in mononuclear phagocytes. Prolonged exposure to the bacterial component, lipopolysaccharide (LPS), increased FLAP gene transcription, mRNA expression, and protein expression in the human monocyte-like THP-1 cell line. Activation and inhibition of the NF-κB pathway modulated LPS induction of FLAP gene expression. An NF-κB-mediated mechanism of action was supported by overexpression of dominant-negative IκBα and p50/p65 proteins. EMSA/supershift and DNase I footprint analyses revealed that p50 binds to an NF-κB site located in the proximal FLAP promoter, while chromatin immunoprecipitation assays demonstrated that LPS induced binding of p50 but not of p65. Moreover, EMSA/supershift analyses demonstrated that LPS induced time-dependent binding of THP-1 nuclear extracts (containing p50) to this promoter region. Mutation of the NF-κB site decreased basal promoter activity and abolished the p50- and p65-associated induction. EMSA/supershift analyses also demonstrated that LPS induced binding of THP-1 nuclear extracts [containing CCAAT/enhancer binding protein (C/EBP)-α, -δ, and -ε] to a C/EBP site located adjacent to the NF-κB site in the FLAP promoter. We conclude that LPS enhances FLAP gene expression via both NF-κB- and C/EBP-mediated transcriptional mechanisms in mononuclear phagocytes.

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