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Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease.

ABSTRACT: To evaluate the inflammatory state in Crohn's disease (CD) patients and correlate it with genetic background and microbial spreading.By means of flow cytometry, production of tumor necrosis factor-alpha (TNF-?) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis (UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants (R702W, G908R and L1007Pfs*2) and basal production of TNF-? was correlated to NOD2 genotype. Also, production of TNF-? was correlated to plasmatic levels of LPS Binding Protein (LBP), soluble (s) CD14 and to the activity state of the disease.The patients with CD were characterized by a significantly higher monocyte basal expression of TNF-? compared with healthy subjects and UC patients, and after stimulation with Pam3CSK4 (ligand of TLR2/1) and MDP-L18 (ligand of NOD2) this difference was maintained, while other microbial stimuli (LPS, ligand of TLR4 and PolyI:C, ligand of TLR3) induced massive activation in CD monocytes as well as in UC and in healthy control cells. There was no significant difference in the production of TNF-? between patients who carried CD-associated heterozygous or homozygous variants in NOD2 and patients with wild type NOD2 genotype. Although serum LBP levels have been shown to correlate positively with the state of activity of the disease, TNF-? production did not show a clear correlation with either LBP or sCD14 levels in plasma. Moreover, no clear correlation was seen between TNF-? production and activity indices in either CD or UC.Peripheral monocytes from CD express higher basal and stimulated TNF-? than controls, regardless of NOD2 genotype and without a clear correlation with disease activity.

SUBMITTER: Loganes C

PROVIDER: S-EPMC5107593 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease.

Loganes Claudia C Pin Alessia A Naviglio Samuele S Girardelli Martina M Bianco Anna Monica AM Martelossi Stefano S Tommasini Alberto A Piscianz Elisa E

World journal of gastroenterology 20161101 41

<h4>Aim</h4>To evaluate the inflammatory state in Crohn's disease (CD) patients and correlate it with genetic background and microbial spreading.<h4>Methods</h4>By means of flow cytometry, production of tumor necrosis factor-alpha (TNF-α) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis (UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common <i>NOD2</i> variants (R702W, G908R a ...[more]

PMID: 27895399

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Project description:Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFN?/? activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: "T1IFN undetectable (T1IFN ND) or IFN?/? >1.3" (n = 9) and "T1IFN detectable but IFN?/? ? 1.3" (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: "T1IFN ND," "T1IFN detected and IFN?/? ? 1.3," and "IFN?/? >1.3." Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFN?/? >1.3 group were unlikely to express JAK1 and IFI27 (p < 0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ? 0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from nine patients. This pattern most strongly associated with the IFN?/?>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFN?/? >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.

Dataset Information

Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease.

Publications

Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease.

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