Olof Grip

Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C hi monocyte precursors

Macrophages (mφ) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete mφ populations carry out these distinct functions or if resident mφ change during inflammation. We show here that most resident mφ in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCIIhi, but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1int cells is present in resting colon and it expands during experimental colitis. Ly6ChiCCR2+ monocytes can give rise to all mφ subsets in both healthy and inflamed colon and we show that the CX3CR1int pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1hi mφ. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory mφ. Phenotypic analysis of human intestinal mφ indicates that analogous processes occur in the normal and Crohns disease ileum. These studies show for the first time that resident and inflammatory mφ in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.

Atorvastatin activates PPAR-gamma and attenuates the inflammatory response in human monocytes.

ObjectiveTo investigate the ability of statins to activate the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) in primary human monocytes in culture.Materials and methodsHuman peripheral monocytes were incubated with atorvastatin (0.1–10 μmol/l) for up to 24 hours. PPAR-γ expression was analysed by electrophoretic mobility shift assay. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assays, and oxygen consumption was determined polarographically with a Clark-type oxygen electrode.ResultsWe found that atorvastatin activates PPAR-γ and inhibits the production of tumour necrosis factor-alpha up to 38% (p < 0.05), monocyte chemoattractant protein-1 up to 85% (p < 0.05), and gelatinase B up to 73% (p < 0.05), in a concentration-dependent manner. Moreover, atorvastatin shows concentration-dependent inhibition of cellular oxygen consumption up to 41 %.ConclusionsThese findings contribute to the growing knowledge of the anti-inflammatory effects of statins, and have led us to the suggestion that statins may control inflammatory responses by the regulation of intracellular lipid homeostasis.

Budd-Chiari syndrome in Sweden : epidemiology, clinical characteristics and survival - an 18-year experience.

Background: The exact incidence and prevalence of Budd‐Chiari syndrome (BCS) is unknown in the general population. Published reports differ in terms of the clinical characteristics, effects of therapy and survival.

Pravastatin down-regulates inflammatory mediators in human monocytes in vitro

There is experimental evidence that pravastatin, which is designed to inhibit the rate-limiting enzyme of cholesterol synthesis, can affect cell metabolism and proliferation. We therefore studied the effects of pravastatin on the generation of inflammatory mediators in non-stimulated and stimulated primary human monocytes in vitro. In our experimental model, pravastatin induced a dose-dependent inhibition of monocyte cholesterol synthesis (up to 67%), up-regulation of low density lipoprotein receptor mRNA (by about 35%) and reduction in intracellular cholesterol accumulation. In parallel, exposure of non-stimulated monocytes to various doses of pravastatin resulted in inhibition of monocyte chemoattractant protein-1 protein expression (up to 15-fold), reduction of tumour necrosis factor alpha (TNF-alpha) levels (up to 2.4-fold) and a total loss of metalloproteinase-9 activity in stimulated cells. Pravastatin at concentrations of 5, 100 and 500 microM caused an inhibition of TNF-alpha-induced cellular oxygen consumption from 2. 4- to 5.5-fold. These data extend the findings of potential anti-inflammatory actions of statins and also suggest the possibility for pravastatin use in a broader spectrum of inflammatory situations.

Diet in the aetiology of ulcerative colitis: A European prospective cohort study

Background/Aims: The causes of ulcerative colitis are unknown, although it is plausible that dietary factors are involved. Case-control studies of diet and ulcerative colitis are subject to recall biases. The aim of this study was to examine the prospective relationship between the intake of nutrients and the development of ulcerative colitis in a cohort study. Methods: The study population was 260,686 men and women aged 20–80 years, participating in a large European prospective cohort study (EPIC). Participants were residents in the UK, Sweden, Denmark, Germany or Italy. Information on diet was supplied and the subjects were followed up for the development of ulcerative colitis. Each incident case was matched with four controls and dietary variables were divided into quartiles. Results: A total of 139 subjects with incident ulcerative colitis were identified. No dietary associations were detected, apart from a marginally significant positive association with an increasing percentage intake of energy from total polyunsaturated fatty acids (trend across quartiles OR = 1.19 (95% CI = 0.99–1.43) p = 0.07). Conclusions: No associations between ulcerative colitis and diet were detected, apart from a possible increased risk with a higher total polyunsaturated fatty acid intake. A biological mechanism exists in that polyunsaturated fatty acids are metabolised to pro-inflammatory mediators.

The epidemiology and clinical features of portal vein thrombosis: a multicentre study

Aliment Pharmacol Ther 2010; 32: 1154–1162

Body Mass Index and the Risk for Crohn's Disease and Ulcerative Colitis: Data From a European Prospective Cohort Study (The IBD in EPIC Study)

OBJECTIVES:Obesity is associated with a proinflammatory state that may be involved in the etiology of inflammatory bowel disease (IBD), for which there are plausible biological mechanisms. Our aim was to perform the first prospective cohort study investigating if there is an association between obesity and the development of incident IBD.METHODS:A total of 300,724 participants were recruited into the European Prospective Investigation into Cancer and Nutrition study. At recruitment, anthropometric measurements of height and weight plus physical activity and total energy intake from validated questionnaires were recorded. The cohort was monitored identifying participants who developed either Crohns disease (CD) or ulcerative colitis (UC). Each case was matched with four controls and conditional logistic regression used to calculate odds ratios (ORs) for body mass index (BMI) adjusted for smoking, energy intake, and physical activity.RESULTS:In the cohort, 177 participants developed incident UC and 75 participants developed incident CD. There were no associations with the four higher categories of BMI compared with a normal BMI for UC (Ptrend=0.36) or CD (Ptrend=0.83). The lack of associations was consistent when BMI was analyzed as a continuous or binary variable (BMI 18.5<25.0 vs. ≥25 kg/m2). Physical activity and total energy intake, factors that influence BMI, did not show any association with UC (physical activity, Ptrend=0.79; total energy intake, Ptrend=0.18) or CD (physical activity, Ptrend=0.42; total energy, Ptrend=0.11).CONCLUSIONS:Obesity as measured by BMI is not associated with the development of incident UC or CD. Alternative measures of obesity are required to further investigate the role of obesity in the development of incident IBD.

Increased subpopulations of CD16+ and CD56+ blood monocytes in patients with active Crohn's disease

Background Circulating monocytes may be subdivided according to the presence or absence of the Fc&ggr; receptor CD16 and the neural cell adhesion molecule CD56. Monocytes classified into these subpopulations are characterized by distinct phenotypic and functional features. We hypothesized that patients with active Crohns disease differ in their peripheral monocyte subpopulations. Methods Using flow cytometry we investigated the expression of CD16 and CD56 on circulating monocytes in 11 patients with active Crohns disease and 11 controls. These monocyte subpopulations were then analyzed for expression of the chemokine receptor fractalkine, CX3CR1, and the monocyte chemoattractant protein‐1, CCR2. Results We found a median 3.7‐fold increase in the number of CD16+ monocytes related to the population with high expression of the pattern recognition receptor CD14 compared to that in the controls (P < 0.001). By studying the percentage of monocytes expressing CX3CR1, and their relative fluorescence intensity (RFI), we found significant differences, with both the highest percentage and the highest RFI in the CD14lowCD16+ subpopulation, whereas the CD14highCD16+ subgroup represented an intermediate population. Inversely, CCR2 expression was highest in the populations with high expression of CD14, whereas the CD14lowCD16+ subpopulation showed the lowest percentage and the lowest RFI for CCR2. We found the percentage of CD14+CD56+ monocytes in patients with active Crohns disease to be increased 2.7 times compared to the controls (P = 0.011). Conclusions These results show that subsets of peripheral monocytes with a more mature phenotype are expanded in patients with active Crohns disease. (Inflamm Bowel Dis 2006)

Serological markers predict inflammatory bowel disease years before the diagnosis

Objective Anti-neutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae mannan antibodies (ASCAs) have been detected in the serum of patients with ulcerative colitis (UC) and Crohns disease (CD) and their unaffected family members. The aim of this study was to establish the value of serological markers as predictors of UC and CD. Design Individuals who developed CD or UC were identified from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. At recruitment, none of the participants had a diagnosis of CD or UC. For each incident case, two controls were randomly selected matched for centre, date of birth, sex, date of recruitment and time of follow-up. Serum of cases and controls obtained at recruitment were analysed for ASCA IgG, ASCA IgA, perinuclear anti-neutrophil cytoplasmic antibody (pANCA), antibodies against Escherichia coli outer membrane porin C (OmpC) and flagellin CBir1. Conditional logistic regression was used to determine risk of CD and UC. Receiver operating characteristic curves were constructed to test accuracy. Results A total of 77 individuals were diagnosed with CD and 167 with UC after a mean follow-up of 4.5 (SD 3.2) and 4.4 (SD 3.1) years following blood collection, respectively. Combinations of pANCA, ASCA, anti-CBir1 and anti-OmpC were most accurate in predicting incident CD and UC (area under curve 0.679 and 0.657, respectively). The predictive value of the combination of markers increased when time to diagnosis of CD or UC decreased. Conclusion A panel of serological markers is able to predict development of CD and UC in individuals from a low-risk population.

Macrophages in inflammatory bowel disease

Blood monocytes which differentiate into tissue macrophages, are unique in that they can not only initiate immune responses but can also be effector cells which contribute to the resolution of these responses. There is no single activation phenotype, and macrophages can be induced to differentiate into cells that either exacerbate or inhibit acute inflammation. Similarly, these cells can promote, deviate or suppress adaptive immune responses. This review focuses on the mechanisms that have been implicated in the recruitment, activation and differentiation of inflammatory monocytes/macrophages in chronic inflammatory bowel diseases, i.e. ulcerative colitis and Crohns disease. These mechanisms might provide attractive targets for novel therapies.