interleukin-8 and Irritable-Bowel-Syndrome

To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk.. We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry.. The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes.. Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cytokines; Female; Genome-Wide Association Study; Humans; Interleukin-10; Interleukin-4; Interleukin-6; Interleukin-8; Irritable Bowel Syndrome; Male; Middle Aged; Receptors, Interleukin; Receptors, Interleukin-1 Type I; Tumor Necrosis Factor Ligand Superfamily Member 15; Tumor Necrosis Factor-alpha; Young Adult

OBJECTIVE. The role of adipokines such as resistin, leptin, and adiponectin could be pivotal in the molecular crosstalk between the inflamed intestine and the surrounding mesenteric adipose tissue. Our aims were to a) evaluate their circulating concentrations in patients with active celiac disease (ACD) and compare them to those in patients with diarrhea-predominant irritable bowel syndrome (IBS-d) and healthy subjects; b) establish the impact of genetic variability in resistin; and c) evaluate whether a 1-year gluten-free diet (GFD) modifies circulating concentrations of resistin, leptin, and adiponectin in celiac patients. MATERIAL AND METHODS. The study included 34 ACD patients, 29 IBS-d patients, and 27 healthy controls. Circulating concentrations of resistin, leptin, adiponectin, IL-6, and IL-8 were evaluated at the time of enrollment. Resistin +299 G/A polymorphism was also analysed. In CD patients, biochemical measurements were repeated after a 1-year GFD. RESULTS. Along with higher IL-6 and IL-8 plasma levels, higher resistin and adiponectin concentrations were found in ACD and IBS-d patients compared with controls (p: 0.0351 and p: 0.0020, respectively). Resistin values proved to be predictable from a linear combination of IL-8 and +299 polymorphism. GFD affected resistin (p: 0.0009), but not leptin and adiponectin concentrations. CONCLUSIONS. Our data suggest that these adipokines are involved in modulating inflammatory processes in both CD and IBS-d patients. Alterations in the adipokine profile as well as the higher prevalence of the resistin +299 G/A SNP A allele compared to controls support the hypothesis that, at least in well-defined cases of IBS, a genetic component may also be supposed.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Celiac Disease; Diarrhea; Diet, Gluten-Free; Female; Genetic Markers; Humans; Interleukin-6; Interleukin-8; Irritable Bowel Syndrome; Leptin; Linear Models; Longitudinal Studies; Male; Middle Aged; Polymorphism, Single Nucleotide; Resistin; Treatment Outcome

To compare the effects of moxibustion and acupuncture of combined "Biao-Ben" acupoints (Biao indicates pathogenic factors of disease, Ben refers to body constitution) on a rat model of irritable bowel syndrome with diarrhea (IBS-D).. Forty female SD rats were randomly divided into 4 groups：normal group, model group, moxibustion group, and acupuncture group, with 10 rats in each group. The IBS-D rat model was established by administering acute-chronic stress combined with folium sennae gavage for 28 days. Rats in the moxibustion group received moxibustion at bilateral "Zusanli"(ST36), "Guanyuan"(CV4), and "Neiguan"(PC6), while those in the acupuncture group received acupuncture at the same acupoints, both for 15 min every time, once a day. The treatments were administered for 21 days. The loose stool rate was observed. Colonic pain threshold and colonic distension threshold were measured by a self-made balloon catheter. Total distance traveled and grid crossing numbers were observed by open field test. Heart rate variability(HRV) time domain indexes SDANN and PNN50 were acguired by using electrophysiological recorder. Histopathological changes in the colon tissue were observed after HE staining. Contents of interleukin-6(IL-6), IL-8, and tumor necrosis factor-alpha(TNF-α) in serum were detected by ELISA.. Compared with the normal group, rats in the model group showed increased loose stool rate(. Moxibustion of combined "Biao-Ben" acupoints is more effective in regulating HRV and serum IL-6, IL-8, and TNF-α contents in the IBS-D rat model. Based on the combined "Biao-Ben" acupoints method, moxibustion has better therapeutic effects on IBS-D than acupuncture.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; Autonomic Nervous System; Diarrhea; Female; Interleukin-6; Interleukin-8; Irritable Bowel Syndrome; Moxibustion; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

To observe the effect of moxibustion on the regulation of nuclear factor-kappa B (NF-κB) and inflammatory factors by multiple microRNAs (miRNAs) in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), and to explore the anti-inflammatory mechanism of moxibustion on IBS-D.. Twelve of 52 newborn rats were randomly selected into a normal group. The remaining rats were made into IBS-D model. A total of 36 rats with successful model were randomly divided into a model group, a medication group and a moxibustion group, 12 rats in each group. The rats in the medication group were intraperitoneally injected with pyrrolidine dithiocarbamate (PDTC). The rats in the moxibustion group were treated with moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) for 20 min each time. All the intervention was given once a day for 7 days. Before and after modeling as well as after intervention, the body mass, loose stool rate and the minimum volume threshold of abdominal withdrawal reflex (AWR) were measured. After intervention, the contents of serum tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-8 were detected by ELISA method; the morphology of colon tissues was observed by HE staining, and the expressions of miR-155, miR-125b, miR-29b, miR-31, miR-18a and NF-κB p65 mRNA in colon tissues were detected by real-time PCR. The expressions of NF-κB p65, TNF-α, IL-1β and IL-8 protein in colon tissues were detected by immunofluorescence.. After modeling, the body mass and the minimum volume threshold of AWR in the model group were lower than those in the normal group (. The anti-inflammatory mechanism of moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) for IBS-D rats may be related to regulating multiple miRNAs to inhibit NF-κB signal pathway and reduce the expression of inflammatory factors.

Topics: Animals; Diarrhea; Interleukin-8; Irritable Bowel Syndrome; MicroRNAs; Moxibustion; NF-kappa B; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

At present, the most direct method to evaluate mucosal healing in patients with ulcerative colitis (UC) is endoscopy, but it is costly and invasive. Therefore, it is necessary to find a biomarker with low cost, easy access, high sensitivity and specificity as an indicator of UC activity. This study aimed to examine the level of platelet to lymphocyte ratio (PLR) and interleukin-8 (IL-8) in UC patients and evaluate their roles in differential diagnosis and disease activity assessment.. A retrospective study involving 130 UC patients and 141 irritable bowel syndrome (IBS) patients was performed. The UC patients were divided into remission group and active group according to the Modified Mayo score. The receiver operating characteristic curve (ROC) analysis was performed to determine the optimal cutoff value of PLR and IL-8 in differential diagnosis between UC patients and IBS patients.. The levels of WBC, PLR, and IL-8 in UC patients were higher than those compared with IBS controls. The optimal cutoff to differentiate UC and IBS patients was 6.76 109/L, 114.70, and 19.42 pg/mL for WBC, PLR, and IL-8, respectively (sensitivity, 36.9% vs. 83.8% vs. 72.3%; specificity, 83.0% vs. 65.2% vs. 94.3%; AUC, 0.601 vs. 0.815 vs. 0.859). IL-8 had the highest AUC and specificity. Among 130 patients, 75 patients (57.6%) had mucosal inflammation. The cutoff value of IL-8 for predicting disease severity of UC patients was 22.21 pg/mL (AUC: 0.861). The sensitivity, specificity, and Youden index of IL-8 for predicting severe UC were 92.0%, 81.8%, and 0.702, respectively.. PLR and IL-8 showed great performance in distinguishing UC from IBS patients. Moreover, elevated IL-8 level indicated mucosal inflammation, reflecting disease severity in UC patients.

Topics: Biomarkers; Colitis, Ulcerative; Diagnosis, Differential; Humans; Inflammation; Interleukin-8; Irritable Bowel Syndrome; Lymphocytes; Retrospective Studies

Bile acids have recently been associated with the pathogenesis of irritable bowel syndrome (IBS). We therefore evaluated the expression of bile acid receptors in the intestinal mucosa of IBS patients as well as the effects of bile acids on small intestinal epithelial cells.. Intestinal biopsy specimens were obtained from 15 IBS patients and 15 healthy controls. The effects of bile acid stimulation on trans-epithelial electrical resistance (TEER) and permeability in differentiated Caco-2 cells were measured. Proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. mRNA levels of bile acid receptors, including farnesoid X receptor (FXR), and cytokines were determined by real-time reverse transcription-PCR. Caco-2 cells were pre-incubated with the FXR antagonist guggulsterone.. FXR mRNA expression at the terminal ileum was increased in IBS patients. Chenodeoxycholic acid (CDCA) significantly decreased TEER, increased permeability, and increased interleukin-8 (IL-8) release from Caco-2 cells. Pre-incubation with guggulsterone blocked CDCA-mediated IL-8 release; however, the decrease in TEER was not reversed. CDCA-induced IL-6 and IL-8 mRNA levels were blocked by guggulsterone. CDCA increased IL-6, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor release, whereas guggulsterone significantly blocked IL-6 and TNF-α release.. FXR expression was elevated at the terminal ileum in IBS patients. CDCA increased proinflammatory cytokines, while guggulsterone blocked these increases.

Topics: Adult; Aged; Biopsy; Caco-2 Cells; Case-Control Studies; Chenodeoxycholic Acid; Enterocytes; Female; Healthy Volunteers; Humans; Ileum; Interleukin-6; Interleukin-8; Irritable Bowel Syndrome; Male; Middle Aged; Permeability; Pregnenediones; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Tumor Necrosis Factor-alpha

The evidence on the role of gut microbiota in post-infectious irritable bowel syndrome (PI-IBS) is convincing. Lactobacillus spp. positively affect IBS symptoms, although the mechanisms through which probiotics exert their beneficial effects are largely unknown. The aim of the study is to evaluate the role of Lactobacillus casei DG (LC-DG) and its postbiotic (PB) in modulating the inflammatory/immune-response in PI-IBS in an ex-vivo organ culture model.. Ex vivo cultures of ileal and colonic mucosa from 10 PI-IBS, diarrhea predominant subtype (D) patients, and 10 healthy controls (HC) were treated with LPS, LC-DG and PB. Interleukin (IL)-1α, IL-6, IL-8 and IL-10 mRNA levels were assessed by real-time PCR and Toll like receptor 4 (TLR-4) protein expression by Western blotting.. At baseline, IL-1α, IL-6 and IL-8 mRNA levels as well as TLR-4 protein expression were significantly higher while IL-10 mRNA levels were lower in PI-IBS D than in HC in both ileum and colon. LC-DG and PB significantly reduced the mRNA levels of pro-inflammatory cytokines and TLR-4 while increased that of IL-10 after LPS stimulation. The protective effect was more pronounced for PB than LC-DG treatment.. LC-DG and its PB attenuate the inflammatory mucosal response in an ex-vivo organ culture model of PI-IBS D.

Topics: Blotting, Western; Case-Control Studies; Colon; Female; Gastrointestinal Microbiome; Humans; Ileum; In Vitro Techniques; Inflammation; Interleukin-10; Interleukin-1alpha; Interleukin-6; Interleukin-8; Intestinal Mucosa; Irritable Bowel Syndrome; Lacticaseibacillus casei; Lipopolysaccharides; Male; Middle Aged; Organ Culture Techniques; Probiotics; Real-Time Polymerase Chain Reaction; RNA, Messenger; Toll-Like Receptor 4

Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal (GI) disorder, which presents with abdominal pain and changes in the bowel habits. Although the exact cause of IBS remains uncertain, some studies have shown that the inflammation and cytokine imbalance may act as potential etiological factors. The aim of our study is to compare the serum levels of interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-α) in patients with IBS with the healthy controls. The other aim of this study is to evaluate possible association between above-mentioned cytokines and IBS subtypes.. Seventy-four IBS patients diagnosed based on Rome III criteria and 75 gender and age-matched healthy controls were included in this study. Cytokines were measured in the serum using enzyme-linked immunosorbent assays (ELISA).. Patients were classified into groups of IBS with diarrhea (IBS-D): 34, IBS with constipation (IBS-C): 29, and IBS with mixed symptoms (IBS-M): 11. The serum levels of IL-6, IL-8 and TNF-α were significantly higher in patients with IBS as compared to controls (P<0.001). There was no difference in serum levels of cytokines based on IBS subtypes.. Higher serum level of IL-6, IL-8 and TNF-α in IBS suggests an important role of cytokines as immune mediators in the pathogenesis of this functional GI disorder. To understand any association between cytokines and IBS subtypes, further investigations with larger sample sizes are desired.

Topics: Adult; Biomarkers; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Interleukin-8; Irritable Bowel Syndrome; Male; Tumor Necrosis Factor-alpha

Evidence suggests that patients with irritable bowel syndrome (IBS) have an altered cytokine profile, although it is unclear whether cytokines are linked with symptom severity. We aimed to determine whether global serum and mucosal cytokine profiles differ between IBS patients and healthy subjects and whether cytokines are associated with IBS symptoms.. Serum from 144 IBS patients and 42 healthy subjects was analyzed for cytokine levels of interleukin (IL)-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, interferon (IFN)-γ, and tumor necrosis factor (TNF) by MSD MULTI-ARRAY. In total, 109 IBS and 36 healthy sigmoid colon biopsies were analyzed for mRNA expression of IL-8, IL-10, TNF, and FOXP3 by quantitative reverse transcription PCR. Multivariate discrimination analysis evaluated global cytokine profiles. Rectal sensitivity, oroanal transit time, and psychological and gastrointestinal symptom severity were also assessed.. Global cytokine profiles of IBS patients and healthy subjects overlapped, but cytokine levels varied more in IBS patients. Serum levels of IL-6 and IL-8 tended to be increased and levels of IFN-γ tended to be decreased in IBS patients. Mucosal mRNA expression of IL-10 and FOXP3 tended to be decreased in IBS patients. Within both the full study cohort and IBS patients alone, serum level of TNF was associated with looser stool pattern, while subjects with more widespread somatic symptoms had increased serum levels of IL-6. Although neither IBS bowel habit subgroups nor patients with possible post-infectious IBS were associated with distinct cytokine profiles, a small cluster of IBS patients with comparatively elevated immune markers was identified.. Global cytokine profiles did not discriminate IBS patients from healthy subjects, but cytokine profiles were more varied among IBS patients than among healthy subjects, and a small subgroup of patients with enhanced immune activity was identified. Also, association of inflammatory cytokines with some clinical symptoms suggests that immune activation may be of importance in a subset of IBS patients.

Topics: Adult; Case-Control Studies; Colon, Sigmoid; Cytokines; Discriminant Analysis; Female; Forkhead Transcription Factors; Gastrointestinal Transit; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-17; Interleukin-5; Interleukin-8; Irritable Bowel Syndrome; Male; Middle Aged; Multivariate Analysis; Rectum; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Tumor Necrosis Factor-alpha; Young Adult

The present study aimed to explore the correlation between cytokine expression of tumor necrosis factor α (TNF‑α), interleukin (IL)‑8 and IL‑10 with occludin production, abdominal symptoms and psychological factors in patients with irritable bowel syndrome‑associated diarrhea (IBS‑D). A total of 42 IBS‑D patients and 20 healthy controls were included, which were recruited from QiLu Hospital in China. ELISA and immunohistochemical analysis were performed for evaluating the cytokines (TNF‑α, IL‑8 and IL‑10) and occludin protein levels in the peripheral blood mononuclear cells (PBMCs) of all subjects. In addition, the abdominal symptoms and psychological status were assessed in IBS‑D patients. Levels of TNF‑α and IL‑8 in the PBMCs of patients with IBS‑D were significantly higher than those in the controls (P<0.001 and P=0.007, respectively), while IL‑10 levels were significantly reduced in patients with IBS‑D (P=0.047). Occludin production was significantly reduced in patients with IBS‑D as compared with that in the controls (P<0.001). In patients with IBS‑D, levels of TNF‑α and IL‑8 were negatively correlated with occludin levels (r=‑0.34, P=0.028; r=‑0.52, P<0.001, respectively). IL‑10 showed a negative correlation with occludin production (r=0.05, P=0.748). Furthermore, TNF‑α, IL‑8 and IL‑10 levels were significantly correlated with symptoms scores (r=0.74, P<0.001; r=0.55, P<0.001; r=‑0.80, P<0.001, respectively) in patients with IBS‑D. Within the IBS‑D group, TNF‑α expression was significantly increased in patients with a self‑rating depression scale (SDS) score ≥50 (P=0.004) as compared with that in patients with an SDS score <50. Furthermore, IL‑8 was significantly increased in IBS‑D patients with a self‑rating anxiety scale (SAS) or SDS score ≥50 (P=0.016, P=0.008, respectively) as compared with that in patients scoring <50. In conclusion, the results of the present study suggested that in IBS‑D, an imbalance of cytokine production evoked colonic epithelial barrier dysfunction, abdominal symptoms and psychological disorders.

Topics: Adolescent; Adult; Cytokines; Diarrhea; Female; Gene Expression; Humans; Immunohistochemistry; Interleukin-10; Interleukin-8; Irritable Bowel Syndrome; Leukocytes, Mononuclear; Male; Middle Aged; Occludin; Stress, Psychological; Tumor Necrosis Factor-alpha; Young Adult

The intestinal protozoan parasite Blastocystis is one of the most common parasites worldwide in humans and, although its ability to cause human disease has been questioned, some reports have demonstrated that this microorganism is associated to the development of irritable bowel syndrome (IBS) and to a proinflammatory response, in which the expression of some cytokines is unregulated. Since inflammatory cytokine gene polymorphisms might have a role in the pathophysiology of IBS, we assessed the role of single nucleotide polymorphisms (SNPs) for interleukin (IL)-8 and IL-10, in previously collected DNA samples from IBS patients and controls, with or without Blastocystis infection. IL-8+396(G) and IL-10-1082 (A) alleles (p=0.0437 and p=0.0267, respectively), as well as their homozygous (p<0.0001 and p=0.0039, respectively) and IL-8+781(CT) (p=0.0248) genotypes were significantly overrepresented in patients with IBS in comparison with controls. IL-8+396(GG) genotype was relevant because it was associated to IBS (p<0.0001), to Blastocystis (p=0.0025), and to IBS–Blastocystis (p=0.0272). In the latter binomial association, this genotype presented a high contribution (etiological fraction =0.452) and a risk >fourfold to develop IBS. IL-8+781 (T) and IL-10-592 (C) alleles were also associated to Blastocystis and to IBS–Blastocystis, respectively (p=0.0448 and p=0.0166). Our results suggest that some IL-8 and IL-10 SNPs could change individual susceptibility increasing the relative risk in the development of IBS in Blastocystis carriers.

Topics: Adult; Aged; Blastocystis; Blastocystis Infections; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Interleukin-10; Interleukin-8; Irritable Bowel Syndrome; Male; Mexico; Middle Aged; Polymorphism, Single Nucleotide

There is evidence for low-grade inflammation in the pathophysiology of post-infectious irritable bowel syndrome (IBS). We assessed the degree of subclinical intestinal mucosal inflammation in diarrhea-predominant IBS (IBS-D) in a tropical setting.. In a prospective study over 1 year, we investigated 49 patients with IBS-D (cases; median age 34 years (range 18-59); M:F 36:13), diagnosed on Rome III criteria. 14 individuals with a family history of colon cancer (median age 46.5 years (range 23-56); M:F 6:8) were selected as controls. Stools of cases and controls were tested for calprotectin. During colonoileoscopy, serial biopsies were obtained. Mucosal mast cells, neutrophils, eosinophils and lymphocytes/plasma cell infiltrate were quantified. Tissue expression of IL-8 and IL-10 was assessed in biopsies by semi-quantitative RT-PCR.. A history suggestive of an episode of infectious diarrhea (ID) was present in 16/49 cases and 0/14 controls (p = 0.013). In cases, there were significantly more mucosal mast cells in the ileum and all segments of colon and significantly more eosinophils in the cecum. Tissue expression of IL-8 was significantly higher and IL-10 significantly lower in cases compared with controls (target/standard cDNA ratio, median (range) IL-8: 1.25 (0.75-2) vs. 0.85 (0.63-1.3), p < 0.0001, Mann-Whitney U test; IL-10: 0.33 (0-0.63) vs. 0.55 (0.5-0.7), p < 0.0001). There was a significant inverse correlation between IL-8 and IL-10 expression (Pearson correlation, (-) 0.509; p < 0.01).. There was evidence of subclinical intestinal mucosal inflammation in patients with IBS-D. The finding of increased eosinophils is novel, and may be of special relevance to IBS-D in the tropics.

Topics: Adolescent; Adult; Biomarkers; Biopsy; Case-Control Studies; Colon; Colonoscopy; Diarrhea; Eosinophils; Female; Gastroenteritis; Humans; Ileum; Interleukin-10; Interleukin-8; Intestinal Mucosa; Irritable Bowel Syndrome; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Sri Lanka; Tropical Climate; Young Adult

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diagnoses seen by primary care providers and gastroenterologists. Proinflammatory cytokines interleukin (IL)-6 and IL-8 have been found increased in IBS patients. Cytokine gene single nucleotide polymorphisms (SNPs) of IL-8 and IL-10 have not been assessed in Mexican IBS patients. DNA was extracted from peripheral blood leucocytes of 45 IBS unrelated patients and 137 controls. Allele, genotype, and haplotype frequencies were determined by analyzing SNPs of IL-8 and IL-10 genes. IL-8 + 396 G allele (P = 0.02), IL-8 + 396(G/G) and IL-8 + 781(C/T) genotypes (P < 0.001), IL-10 - 1082A allele and IL-10 - 1082(A/A) genotype (P < 0.001) were significantly increased in the IBS group. Haplotypes IL-8 ATCC (P = 0.03) and IL-10 ACC (P < 0.001) were associated with susceptibility to develop IBS. An association of certain polymorphisms of IL-8 and IL-10 in IBS patients compared to controls was demonstrated, suggesting a role of these cytokine SNPs in the pathophysiology of IBS.

Topics: Adult; Alleles; Case-Control Studies; Female; Gene Frequency; Genotype; Humans; Interleukin-10; Interleukin-8; Irritable Bowel Syndrome; Male; Middle Aged; Polymorphism, Single Nucleotide

Irritable bowel syndrome (IBS) is characterized by episodic bouts of abdominal pain, bloating, and altered bowel habit. Accumulating evidence has linked immune activation with IBS, including reports of increases in circulating levels of the proinflammatory cytokine interleukin (IL)-6. However, it is unknown whether IL-6 contributes directly to disease manifestation. As enteric nervous activity mediates motility and secretory function, the aims of this study were to determine the effects of IL-6 on submucosal neurons and related gastrointestinal (GI) function. In these studies, we examined the colons of maternally separated (MS) rats, which exhibit elevated circulating levels of IL-6 in addition to GI dysfunction. To our knowledge, these studies are the first to provide evidence of the sensitivity of submucosal neurons to colonic secretions from MS rats (n = 50, P < 0.05), thus recapitulating clinical biopsy data. Moreover, we demonstrated that the excitatory action is IL-6 dependent. Thereafter, the impact of IL-6 on neuronal and glial activation and absorpto/secretory function was pharmacologically characterized. Other proinflammatory cytokines including IL-8 (n = 30, P > 0.05), IL-1β (n = 56, P > 0.05), and TNF-α (n = 56, P > 0.05) excited fewer neurons. Both muscarinic and nicotinic cholinergic receptors participate in the effect and cause downstream activation of ERK, JAK-STAT, and NF-κB signaling cascades. Functionally, IL-6 increases transepithelial resistance and enhances neurally and cholinergically mediated ion transport. These data provide a role for IL-6 in colonic secretory functions and relate these effects to GI dysfunction in an animal model of IBS, thereby elucidating a potential relationship between circulating levels of IL-6 and aberrant GI function.

Topics: Acetylcholine; Animals; Cholinergic Agonists; Colon; Female; Ganglia; In Vitro Techniques; Interleukin-1beta; Interleukin-6; Interleukin-8; Irritable Bowel Syndrome; Male; Maternal Deprivation; Mitogen-Activated Protein Kinases; Neurons; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-6; Recombinant Proteins; Signal Transduction; STAT3 Transcription Factor; Submucous Plexus; Tumor Necrosis Factor-alpha

Chitinase 3-like-1 (CHI3L1/YKL-40) is a protein secreted from restricted cell types including colonic epithelial cells (CECs) and macrophages. CHI3L1 is an inflammation-associated molecule, and its expression is enhanced in persons with colitis and colon cancer. The biological function of CHI3L1 on CECs is unclear. In this study, we investigated the role of CHI3L1 on CECs during the development of colitis-associated neoplasia. We analyzed colonic samples obtained from healthy persons and from persons with ulcerative colitis with or without premalignant or malignant changes. DNA microarray and RT-PCR analyses significantly increased CHI3L1 expression in non-dysplastic mucosa from patients with inflammatory bowel disease (IBD) who had dysplasia/adenocarcinoma compared with that in healthy persons and in patients with IBD who did not have dysplasia. As determined by IHC, CHI3L1 was expressed in specific cell types in the crypts of colonic biopsies obtained from patients with ulcerative colitis who have remote dysplasia. Purified CHI3L1 efficiently activated the NF-κB signaling pathway and enhanced the secretion of IL-8 and TNF-α in SW480 human colon cancer cells. In addition, colon cancer cell proliferation and migration were significantly promoted in response to CHI3L1 in these cells. In summary, CHI3L1 may contribute to the proliferation, migration, and neoplastic progression of CECs under inflammatory conditions and could be a useful biomarker for neoplastic changes in patients with IBD.

Topics: Adipokines; Biomarkers, Tumor; Cell Movement; Cells, Cultured; Chitinase-3-Like Protein 1; Colitis, Ulcerative; Colon; Colorectal Neoplasms; Dose-Response Relationship, Drug; Epithelial Cells; Female; Humans; Interleukin-8; Intestinal Mucosa; Irritable Bowel Syndrome; Lectins; Male; Middle Aged; NF-kappa B; Precancerous Conditions; Tumor Necrosis Factor-alpha

To systematically examine mucosal biopsies for differences in cytokine gene expression and protein secretion.. The study included 59 females with irritable bowel syndrome (IBS) and 39, otherwise healthy, female volunteers presenting for colonoscopy. Colonic biopsies from subsets were studied by microarray analysis (IBS, n=9; controls, n=8), quantitative reverse transcription-polymerase chain reaction (qRT-PCR) (IBS, n=22; controls, n=21), and ex vivo biopsy culture (IBS, n=28, controls, n=10). Biopsies from patients with active colitis were used as inflammatory disease controls.. While gene array analysis revealed extensive overlapping between controls and IBS patients, reduced expression of genes linked to chemokine function was evident among the IBS patients alone. Differential expression was confirmed by qRT-PCR or ex vivo biopsy culture for 5 out of 6 selected genes. Reduced secretion of chemokines (IL-8, CXCL-9 and MCP-1) but not pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) was established on the basis of the ex vivo biopsy cultures. These findings were in marked contrast to the IBD patients who demonstrated increased production of both chemokines and pro-inflammatory cytokines.. Despite the expected heterogeneity of the disorder, differences in mucosal chemokine signalling were evident in this cross-sectional study of IBS patients at the level of both gene expression and protein secretion, with IBS patients demonstrating a consistent deficit in the expression and secretion of chemokines known to play a critical role in mucosal defence.

Topics: Adolescent; Adult; Aged; Chemokine CCL2; Chemokine CXCL9; Colonoscopy; Cytokines; Female; Gene Expression; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Intestinal Mucosa; Irritable Bowel Syndrome; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

Irritable bowel syndrome (IBS) is a functional disorder, which has recently been linked to immune activation. We tested the hypothesis that the pro-inflammatory cytokine profile in IBS is driven by the cholinergic system and determined if the responses are mediated by muscarinic receptors.. Eighty-eight subjects took part in two studies, 37 IBS patients (Rome II), 14 depressed patients, and 37 healthy volunteers. Eighteen IBS patients had diarrhea predominant IBS, 14 were alternators, and 5 were predominantly constipated. In study 1, blood was drawn for baseline measurement of growth hormone (GH) and cytokines IL-6, IL-8, and IL-10. Pyridostigmine 120 mg was administered orally and further blood sampling took place for 180 min. In study 2, patients with IBS, depressed patients, and healthy subjects underwent the pyridostigmine test on two separate occasions with procyclidine (antimuscarinic) pre-treatment on one test occasion. Both GH and IL-6 were monitored.. In study 1, baseline IL-6 (P= 0.003) and IL-8 levels (P= 0.001) were higher in IBS than in controls. Pyridostigmine stimulated the release of IL-6 and GH, but not IL-8 or IL-10; these responses were significantly augmented in IBS patients relative to controls. The IL-6 level following pyridostigmine administration correlated significantly with the symptom score (P < 0.01). In study 2, IL-6 rose following pyridostigmine in IBS but not depression and procyclidine blocked the rise. The GH response was abolished by procyclidine in all three groups.. IBS and major depression are characterized by a pro-inflammatory profile, whereas IBS patients alone exhibit an exaggerated muscarinic receptor-mediated IL-6 response.

Topics: Abdominal Pain; Administration, Oral; Adolescent; Adult; Biomarkers; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Irritable Bowel Syndrome; Male; Middle Aged; Muscarinic Antagonists; Pain Measurement; Procyclidine; Prognosis; Pyridostigmine Bromide; Radioimmunoassay; Receptors, Muscarinic

Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles.. A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge.. Cortisol and the proinflammatory cytokines interleukin (IL)-6 (together with its soluble receptor) and IL-8 were elevated in all IBS subgroups (diarrhea predominant, constipated, and alternators), although the elevation was most marked in the constipated subgroup. There was no alteration in the anti-inflammatory cytokine IL-10. Following CRH infusion, an exaggerated release of both ACTH and cortisol was observed in patients with IBS. There was a significant correlation between the ACTH response (deltaACTH) and the IL-6 levels. A similar relationship existed between the deltaACTH/deltacortisol ratio and the IL-6 levels. Dexamethasone suppression of cortisol was similar in patients and controls.. IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.

Topics: Adrenocorticotropic Hormone; Adult; Alcohol Drinking; Biomarkers; Cytokines; Dexamethasone; Female; Humans; Hypothalamo-Hypophyseal System; Interleukin-10; Interleukin-6; Interleukin-8; Intestines; Ireland; Irritable Bowel Syndrome; Male; Pain; Reference Values