The −A2518G Polymorphism of Monocyte Chemoattractant Protein-1 Is Associated With Crohn's Disease

Palmieri, Orazio; Latiano, Anna; Salvatori, Enrica; Valvano, Maria Rosa; Bossa, Fabrizio; Latiano, Tiziana; Corritore, Giuseppe; Mauro, Lazzaro Di; Andriulli, Angelo; Annesec, Vito

doi:10.1038/ajg.2010.4

Cited by 25 publications

(19 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[41] The CCR2 −/− model is relevant to CD pathogenesis because CCR2+ lamina propria lymphocytes are a specific feature of ileal CD [57] and polymorphisms in CCR2 have been associated with CD in several studies. [58], [59] On this basis we suggest that pharmacologic blockade of this receptor, which has been demonstrated in mice, [60] may provide a novel pathway for therapeutic intervention in CD. In a similar vein, by controlling inflammation using anti-TNF-α mAb, we reduced dysbiosis, unmasking an effect of this therapy not previously appreciated.…”

Section: Discussionmentioning

confidence: 81%

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’s Disease

et al. 2012

View full text Add to dashboard Cite

Background and AimsUnderstanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn’s Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis.MethodsWe induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI;0.1 mg/mouse), or high dose indomethacin (HDI;1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype.ResultsModerate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% Gram + Firmicutes to >95% Gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2−/−, and reduced dysbiosis in ileitis-resistant CCR2−/− mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion.ConclusionsAcute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD.

show abstract

Section: Discussionmentioning

confidence: 81%

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’s Disease

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Chemokines have distinct chemoattractant properties dictated by their cell-specific expression, differential cytokine regulation, and chemokine receptor cell-specific expression, abundance, and specificity. The monocyte chemoattractant protein MCP-1 (CCL2), which is NF-κB-inducible, mediates monocytes chemoattraction and bone marrow egress, and had been genetically associated with CD (44, 45) showed a 20- and 30-fold increase in aUC and aCD respectively compared to NS (Figure 4A, Table II). In turn, the MCP-1 chemokine receptor CCR2, which is a marker for activated monocytes and macrophages, showed a significantly 20- and 40-fold higher expression in aUC and aCD respectively compared to NS (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

Immune markers and differential signaling networks in ulcerative colitis and Crohnʼs disease

Christophi

Rong

Holtzapple

et al. 2012

Inflammatory Bowel Diseases

109

View full text Add to dashboard Cite

Background & Aims Cytokine signaling pathways play a central role in the pathogenesis of inflammatory bowel disease (IBD). Ulcerative colitis (UC) and Crohn’s disease (CD) have unique as well as overlapping phenotypes, susceptibility genes, and gene expression profiles. This study aimed to delineate patterns within cytokine signaling pathways in colonic mucosa of UC and CD patients, explore molecular diagnostic markers, and identify novel immune-mediators in IBD pathogenesis. Methods We quantified 70 selected immune genes that are important in IBD signaling from formalin-fixed, paraffin-embedded (FFPE) colon biopsy samples from normal control subjects and UC and CD patients having either severe colitis or quiescent disease (n=98 subjects). We utilized and validated a new modified real-time RT-PCR technique for gene quantification. Results Expression levels of signaling molecules including IL-6/10/12/13/17/23/33, STAT1/3/6, T-bet, GATA3, FOXp3, SOCS1/3, and downstream inflammatory mediators such as chemokines CCL-2/11/17/20, oxidative stress inducers, proteases, and mucosal genes were differentially regulated between UC and CD and between active and quiescent disease. We also document the possible role of novel genes in IBD, including SHP-1, IRF-1,TARC, Eotaxin, NOX2, Arginase I, and ADAM 8. Conclusions This comprehensive approach to quantifying gene expression provides insights into the pathogenesis of IBD by elucidating distinct immune signaling networks in CD and UC. Furthermore, this is the first study demonstrating that gene expression profiling in FFPE colon biopsies might be a practical and effective tool in the diagnosis and prognosis of IBD and may help identify molecular markers that can predict and monitor response to individualized therapeutic treatments.

show abstract

“…A single nucleotide polymorphism (SNP) is located at the −2518 position of the MCP-1 promoter region (rs1024611), which is genetically associated with several autoimmune diseases [19]–[21]. The SNP genotypes are also associated with MCP-1 gene expression in human pancreatic islets [22].…”

Section: Resultsmentioning

confidence: 99%

Chemokine (C-C Motif) Ligand 2 (CCL2) in Sera of Patients with Type 1 Diabetes and Diabetic Complications

et al. 2011

View full text Add to dashboard Cite

BackgroundChemokine (C-C motif) ligand 2 (CCL2), commonly known as monocyte chemoattractant protein-1 (MCP-1), has been implicated in the pathogenesis of many diseases characterized by monocytic infiltration. However, limited data have been reported on MCP-1 in type 1 diabetes (T1D) and the findings are inconclusive and inconsistent.MethodsIn this study, MCP-1 was measured in the sera from 2,472 T1D patients and 2,654 healthy controls using a Luminex assay. The rs1024611 SNP in the promoter region of MCP-1 was genotyped for a subset of subjects (1764 T1D patients and 1323 controls) using the TaqMan-assay.ResultsSubject age, sex or genotypes of MCP-1 rs1024611SNP did not have a major impact on serum MCP-1 levels in either healthy controls or patients. While hemoglobin A1c levels did not have a major influence on serum MCP-1 levels, the mean serum MCP-1 levels are significantly higher in patients with multiple complications (mean = 242 ng/ml) compared to patients without any complications (mean = 201 ng/ml) (p = 3.5×10−6). Furthermore, mean serum MCP-1 is higher in controls (mean = 261 ng/ml) than T1D patients (mean = 208 ng/ml) (p<10−23). More importantly, the frequency of subjects with extremely high levels (>99th percentile of patients or 955 ng/ml) of serum MCP-1 is significantly lower in the T1D group compared to the control group (odds ratio = 0.11, p<10−33).ConclusionMCP-1 may have a dual role in T1D and its complications. While very high levels of serum MCP-1 may be protective against the development of T1D, complications are associated with higher serum MCP-1 levels within the T1D group.

show abstract

The −A2518G Polymorphism of Monocyte Chemoattractant Protein-1 Is Associated With Crohn's Disease

Abstract: The -A2518G polymorphism seems to be associated with CD but does not influence MCP-1 plasma levels, which in contrast are increased in UC and CD with extensive colonic involvement.

Cited by 25 publications

References 40 publications

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’s Disease

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’s Disease

Immune markers and differential signaling networks in ulcerative colitis and Crohnʼs disease

Chemokine (C-C Motif) Ligand 2 (CCL2) in Sera of Patients with Type 1 Diabetes and Diabetic Complications

Contact Info

Product

Resources

About