interleukin-8 and Pancreatitis--Chronic

Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T follicular helper 2 cells) are hypothesized to drive the inflammatory reaction. The B-cell response is characterized by an oligoclonal expansion of plasmablasts, with dominant clones that vary among patients and distinct clones that emerge at the time of relapse. Although the precise role of IgG4 in this condition remains uncertain, recent studies suggest that other IgG subclasses (eg, IgG1) may mediate the immune reactions, whereas IgG4 represents a response to dampen excessive inflammation. A recent study of type 2 autoimmune pancreatitis highlights the role of CXCL8 (alias IL-8), with duct epithelium and infiltrating T lymphocytes expressing this chemokine; the latter may contribute to the distinct form of neutrophilic inflammation in this disease. The review also highlights other forms of mass-forming chronic pancreatitis: follicular pancreatitis, groove pancreatitis, and those associated with rheumatologic diseases.

Topics: Antibodies, Neoplasm; Autoimmune Diseases; Carcinoma, Pancreatic Ductal; Fibrosis; Humans; Immunoglobulin G; Inflammation; Interleukin-8; Neoplasm Proteins; Pancreatic Neoplasms; Pancreatitis, Chronic; Plasma Cells; T-Lymphocytes, Regulatory; Th2 Cells

To determine clinical features and some mechanisms of osteosarcopenia development in patients with chronic pancreatitis (CP).. A casecontrol study was conducted on the basis of the Saratov State Clinical Hospital 5 in 20152018 of patients with CP. In a study of 161 patients with CP included, the control group 30 healthy individuals. Patients were divided into groups according to the etiology of CP: 79 with toxic-metabolic CP, 82 with biliary CP. To determine the risks of low-energy fractures, 154 patients were tested with the Fracture risk assessment tool (FRAX). Along with the standard examination, 30 patients with CP dual-energy X-ray absorptiometry was performed. To assess the state of skeletal muscles, body mass index was determined, hand-held dynamometry was performed, and a set of Short Physical Performance Battery (SPPB) tests was used. Along with the assessment of traditional risk factors for osteosarcopenia gender, age, state of reproductive function in women, body mass index, functional state of the pancreas (pancreas) the quantitative content of interleukins (IL)-2, 6, 8 in in colonic biopsies was analyzed by enzyme-linked immunosorbent assay (ELISA).. Bone disorders, according to densitometry, was detected in 70.0% of patients with CP, in 13.3% of the control group. Presarcopenia was detected in 62 (38.5%) patients with CP, sarcopenia in 34 (21.1%), in the control group presarcopenia and sarcopenia were not detected. Sarcopenia was statistically significantly more common in toxic-metabolic CP than in biliary CP (2=11.6; p0.001). Correlations of the lumbar spine T-score and IL-6 (r=-0.29; p=0.03), IL-8 (r=-0.29; p=0.04) were revealed. Correlations between sarcopenia and the concentration of cytokines in the in the colon mucosa in CP were determined (IL-2: r=0.44; p0.001; IL-6: r=0.48; p0.001; IL-8: r=0.42; p0.001).. The development of osteopenia and sarcopenia syndromes in CP is interrelated and associated with both traditional risk factors and an increased concentration of cytokines in the in the colon mucosa.. Цель. Определить частоту, клинические особенности и некоторые механизмы развития остеосаркопении у пациентов с хроническим панкреатитом (ХП). Материалы и методы. Проведено исследование случайконтроль на базе городского гастроэнтерологического центра ГУЗ Саратовская городская клиническая больница №5 в 20152018 гг. пациентов с ХП. В исследование включен 161 пациент с ХП, в контрольную группу 30 здоровых лиц. Пациенты разделены с учетом этиологии ХП: 79 с токсико-метаболическим ХП, 82 с билиарнозависимым. Для определения рисков низкоэнергетических переломов 154 пациентам выполнено тестирование Fracture risk assessment tool (FRAX). Наряду со стандартным обследованием 30 пациентам с ХП выполнена двухэнергетическая рентгеновская денситометрия. Для оценки состояния скелетной мускулатуры определяли индекс массы тела, выполняли кистевую динамометрию, для оценки физической работоспособности набор тестов Short Physical Performance Battery (SPPB). Наряду с оценкой традиционных факторов риска остеосаркопении пол, возраст, состояние репродуктивной функции у женщин, индекс массы тела, функциональное состояние поджелудочной железы проведен анализ количественного содержания в колонобиоптатах интерлейкина (ИЛ)-2, ИЛ-6, ИЛ-8 методом иммуноферментного анализа. Результаты. Остеодефицит по данным денситометрии выявлен у 70,0% пациентов с ХП, у 13,3% лиц контрольной группы. Пресаркопения выявлена у 62 (38,5%) пациентов с ХП, саркопения у 34 (21,1%), в контрольной группе пресаркопении и саркопении не выявлено. Саркопения встречалась статистически значимо чаще при токсико-метаболическом ХП, чем при билиарнозависимом ХП (2=11,6; p0,001). Выявлены корреляции Т-критерия поясничного отдела позвоночника и ИЛ-6 (r=-0,29; p=0,03), ИЛ-8 (r=-0,29; p=0,04). Определены корреляционные связи саркопении и концентрации цитокинов в слизистой оболочке толстой кишки при ХП (ИЛ-2: r=0,44; p0,001; ИЛ-6: r=0,48; p0,001; ИЛ-8: r=0,42; p0,001). Заключение. Развитие синдромов остеопении и саркопении при ХП взаимосвязано и ассоциировано как с традиционными факторами риска, так и с повышенной концентрацией цитокинов в слизистой оболочке толстой кишки.

Topics: Bone Density; Female; Humans; Interleukin-2; Interleukin-6; Interleukin-8; Osteoporosis; Pancreatitis, Chronic; Sarcopenia

(Aim) Bacterial infection underlies the pathogenesis of many human diseases, including acute and chronic inflammation. Here, we investigated a possible role for bacterial infection in the progression of chronic pancreatitis. (Materials and Methods) Pancreatic juice was obtained from patients with pancreatic cancer (n = 20) or duodenal cancer/bile duct cancer (n = 16) and subjected to PCR using universal primers for the bacterial 16S ribosomal RNA gene. Bacterial species were identified by PCR using bile samples from four pancreatic cancer patients. PCR products were subcloned into T-vectors, and the sequences were then analyzed. Immunohistochemical and serologic analyses for Enterococcus faecalis infection were performed on a large cohort of healthy volunteers and patients with chronic pancreatitis or pancreatic cancer and on mice with caerulein-induced chronic pancreatitis. The effect of E. faecalis antigens on cytokine secretion by pancreatic cancer cells was also investigated. (Results) We found that 29 of 36 pancreatic juice samples were positive for bacterial DNA. Enterococcus and Enterobacter species were detected primarily in bile, which is thought to be a pathway for bacterial infection of the pancreas. Enterococcus faecalis was also detected in pancreatic tissue from chronic pancreatitis and pancreatic cancer patients; antibodies to E. faecalis capsular polysaccharide were elevated in serum from chronic pancreatitis patients. Enterococcus-specific antibodies and pancreatic tissue-associated E. faecalis were detected in mice with caerulein-induced chronic pancreatitis. Addition of Enterococcus lipoteichoic acid and heat-killed bacteria induced expression of pro-fibrotic cytokines by pancreatic cancer cells in vitro. (Conclusion) Infection with E. faecalis may be involved in chronic pancreatitis progression, ultimately leading to development of pancreatic cancer.

Topics: Adenocarcinoma; Animals; Antibodies, Bacterial; Bacterial Infections; Disease Models, Animal; Enterococcus; Female; Gene Expression Regulation, Neoplastic; Hot Temperature; Humans; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis, Chronic; RNA, Messenger; RNA, Ribosomal, 16S; Teichoic Acids; Vascular Endothelial Growth Factor A

Fibroblasts in the area of fibrosis in chronic pancreatitis and of the desmoplastic reaction associated with pancreatic cancer are now recognised as activated pancreatic stellate cells (PSCs). Recent studies have shown strong expression of fibrinogen, the central protein in the haemostasis pathway, in the stromal tissues of pancreatic cancer and chronic pancreatitis, suggesting that PSCs are embedded in and exposed to abundant fibrinogen in these pathological settings. The effects of fibrinogen on cell functions in PSCs were examined here.. PSCs were isolated from human pancreas tissues of patients undergoing operations for pancreatic cancer, and from rat pancreatic tissues. The effects of fibrinogen on key cell functions and activation of signalling pathways in PSCs were examined.. Fibrinogen induced the production of interleukin 6 (IL6), interleukin 8 (IL8), monocyte chemoattractant protein-1, vascular endothelial growth factor, angiopoietin-1 and type I collagen, but not proliferation or intercellular adhesion molecule-1 expression. Fibrinogen increased alpha-smooth muscle actin expression and induced the activation of nuclear factor-kappaB (NF-kappaB), Akt and three classes of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK)). Fibrinogen-induced IL6 and IL8 production was inhibited by antibodies against alpha(v)beta(3) and alpha(5)beta(1) integrins, suggesting that these integrins worked as counter receptors for fibrinogen in PSCs. In addition, fibrinogen-induced production of these cytokines was abolished by an inhibitor of NF-kappaB, and partially inhibited by inhibitors of ERK and p38 MAPK.. Fibrinogen directly stimulated profibrogenic and proinflammatory functions in PSCs.

Topics: Animals; Cell Movement; Cells, Cultured; Collagen Type I; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinogen; Humans; Integrin alpha5beta1; Integrin alphaVbeta3; Interleukin-6; Interleukin-8; Male; Mice; Mice, Nude; Neoplasm Transplantation; Pancreas; Pancreatic Neoplasms; Pancreatitis, Chronic; Peptide Fragments; Procollagen; Rats; Rats, Wistar; Signal Transduction

Topics: Diagnosis, Differential; Endosonography; Humans; Interleukin-10; Interleukin-1beta; Interleukin-2; Interleukin-4; Interleukin-5; Interleukin-6; Interleukin-8; Interleukins; Pancreatic Neoplasms; Pancreatitis, Chronic; Prospective Studies; Th1 Cells; Th2 Cells

In chronic pancreatitis (CP), both the progressive loss of acinar parenchyma and aggressive fibro-inflammatory reactions ultimately lead to irreversible organ destruction. Dying cells are normally removed by macrophages and elimination is associated with anti-inflammatory cytokine switch. We investigated whether defective clearance of damaged acini by macrophages such as compromised phagocytosis or altered cytokine reaction occurs in CP and thus represents a causative link between acinar loss and fibro-inflammation. In a checkerboard-like co-culture system, we assessed normal and CP macrophages for their phagocytic and cytokine responses to dying pancreatic acinar cells of normal or CP origin by FACS, confocal microscopy, QRT-PCR, and ELISA. In CP, phagocytosis of apoptotic acini by macrophages was not impaired; however, the associated cytokine responses were gradually perturbed. Most interestingly, only normal acini suppressed TGFbeta1 expression and accumulation specifically in normal macrophage cultures, while CP acini lost this ability. Both types of apoptotic acini induced pro-inflammatory cytokine bursts of varying strength in both types of macrophages; however, the most significant difference (more than 50-fold higher expression of IL-1beta, IL-6, and IL-8) was evident between CP/CP and normal/normal combinations, indicating that acinar and macrophage alterations synergistically lead to the ultimate CP-specific bias. In combination with in situ data comparing circulating inflammatory cells to pancreatic resident ones, our results indicate that cytokine expression in inflammatory cells undergoes spatiotemporal modulation, most likely through a successive interplay of acinar, stromal, and circulating factors. Thus, clearance of injured pancreatic acini by macrophages is associated with a unique cytokine reaction which may constitute a basis for progression of SAPE (sentinel acute pancreatitis event) to the irreversible fibro-inflammation in CP.

Topics: Apoptosis; Coculture Techniques; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Macrophages; Microscopy, Confocal; Pancreas; Pancreatitis, Chronic; Phagocytosis; Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

Cytokine regulation may be an important factor in the susceptibility for the development of chronic pancreatitis; transforming growth factor-beta1 (TGF-beta1) plays a central role in the pathogenesis of pancreatic fibrogenesis. The aim of our study was to analyse the relevance of TGF-beta1, interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) polymorphisms in patients with chronic pancreatitis.. of the 83 patients enrolled in the study, 43 were treated medically and 40 patients underwent surgical intervention. Healthy blood donors (n=75) served as controls.. the polymorphisms of TGF-beta1 +869 T--> C and IL-8 -251 T-->A were determined by the ARMS method, while that of TNF-alpha -308 was investigated using NcoI RFLP.. there was a higher frequency (50%) of the TT genotype of TGF-beta1 +869, with a concomitantly higher TGF-beta1 level in the plasma (5.2 +/- 1.7 ng/mL) of patients with chronic pancreatitis than in healthy blood donors (28% and 2.8 +/- 0.9 ng/mL respectively). The number of TT homozygotes differed significantly between the patients who underwent surgical intervention and the controls, and even between the surgical and the non-surgical patients. The frequency of the T/A genotype with higher IL-8 production, was significantly higher in both groups of patients than in the controls (58% and 58% versus 40%). No correlation was found between the TNF-alpha -308 polymorphism and chronic pancreatitis.. correlations of the TGF-beta1 and IL-8 single nucleotide polymorphisms (SNPs) with chronic pancreatitis underline the importance of these cytokines in the pathomechanism of the disease. Moreover, it seems that the TT genotype of +869 TGF-beta1 might be a risk factor for the development of a severe form of chronic pancreatitis, and could serve as a prognostic sign for any future surgical intervention or even repeat surgery. Further studies on a larger group of patients, in addition to a follow-up study, are necessary to confirm this preliminary observation.

Topics: Adult; Aged; Analysis of Variance; Chi-Square Distribution; Enzyme-Linked Immunosorbent Assay; Female; Gene Frequency; Genotype; Humans; Interleukin-8; Male; Middle Aged; Odds Ratio; Pancreatitis, Chronic; Polymorphism, Single Nucleotide; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Pancreatic juice (PJ) [IL-8] has been proposed as a marker for pancreatic diseases. We compared the accuracy of PJ [IL-8] and endoscopic ultrasound (EUS) to diagnose chronic pancreatitis (CP).. 79 patients with symptoms suspicious for CP were enrolled. PJ emptied into the duodenum was collected during an upper endoscopy with IV secretin and [IL-8] was measured. CP was diagnosed when PJ [IL-8] was >20 pg/ml. CP was diagnosed at EUS when >or=4 of the 9 established criteria were present. CP was diagnosed by using composite gold standard: ERCP, histology, CT or MRI, and clinical follow-up (mean 20 months).. 38 patients had CP, whereas 41 patients had no pancreatic disease. To diagnose CP, PJ [IL-8] was significantly less sensitive compared to EUS (47 vs. 71%), but equally accurate (71 vs. 80%) and specific (93 vs. 88%). By combining PJ [IL-8] and EUS, sensitivity and specificity significantly increased to 82% (either IL-8 or EUS positive) and 100% (both IL-8 and EUS positive).. Both PJ [IL-8] and EUS are accurate diagnostic modalities for CP. PJ collection can be performed at the time of EUS. PJ [IL-8] and EUS are complementary with higher sensitivity and specificity when used together.

Topics: Adult; Aged; Endosonography; Female; Humans; Interleukin-8; Male; Middle Aged; Pancreatic Juice; Pancreatitis, Chronic; Prospective Studies; Sensitivity and Specificity

To determine characteristics of a cytokine status in chronic pancreatitis (CP) depending on etiological factor, stage of the disease, complications, therapy. Material and methods. 72 patients had chronic alcoholic pancreatitis (CAP), 38 patients--chronic biliary pancreatitis (CBP). Control group consisted of 20 healthy subjects.. At early stages and height of CAP exacerbation, concentrations of IL-1beta, IL-6, IL-8, TNF-gamma and TNFalpha were elevated (951.1 +/- 104.2 pg/ml; 172.8 +/- 24.3 pg/ml; 432.6 +/- 68.5 pg/ml; 823.3 +/- 97.5 pg/ml; 158.7 +/- 19.6 pg/ml, respectively). Regenerative processes in CP were accompanied with IL-4 elevation to 614.9 +/- 64.6 pg/ml. In CAP without complications and with them the levels of cytokines differed significantly. The level of TGF-beta1 stimulating development of fibrosis was in CAP patients 627.8 +/- 92.2 pg/ml, in CAP patients with complications--796.8 +/- 102.5, in the controls--40.2 +/- 4.6 pg/ml (p < 0.05). In early stages of CBP exacerbation, IL-1beta rose to 527.2 +/- 62.7 pg/ml, IL-6--to 80.9 +/- 11.4 pg/ml, IL-8--to 290.4 +/- 46.8 pg/ml, INF-gamma to 853.3 +/- 91.6 pg/ml; TNF-alpha--to 79.7 +/- 8.3 pg/ml, TGF-beta1--534.1 +/- 78.4 pg/ml. With attenuation of acute syndromes and development ofregeneration, levels of IL-4 went up (226.7 +/- 32.4 pg/ml).. CP is accompanied by increase in cytokine contents depending on the etiological factor, variants of course, stage, presence of complications.

Topics: Adult; Biliary Tract Diseases; Biomarkers; Cytokines; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Interferon-gamma; Interleukin-1; Interleukin-4; Interleukin-6; Interleukin-8; Male; Middle Aged; Pancreatitis, Alcoholic; Pancreatitis, Chronic; Prognosis; Severity of Illness Index; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Cytokine concentration in pancreatic juice of patients with pancreatic disease is unknown. Secretin stimulation allows endoscopic collection of pancreatic juice secreted into the duodenum. We aimed to evaluate the cytokine concentrations in pancreatic juice of patients with abdominal pain to discriminate presence from absence of pancreatic disease.. From January 2003-December 2004, consecutive patients with abdominal pain compatible with pancreatic origin were enrolled. Patients underwent upper endoscopy. Intravenous secretin (0.2 mug/kg) was given immediately before scope intubation. Pancreatic juice collected from the duodenum was immediately snap-frozen in liquid nitrogen until assays were performed. Pancreatic juice levels of interleukin-8, interleukin-6, intercellular adhesion molecule 1, and transforming growth factor-beta 1 were measured by modified enzyme-linked immunosorbent assays. The final diagnosis was made by the primary gastroenterologist on the basis of medical history; laboratory, endoscopic, and imaging studies; and clinical follow-up. Fisher exact test and Kruskal-Wallis rank sum test were used for statistical analysis.. Of 130 patients screened, 118 met the inclusion criteria. Multivariate analysis revealed that only interleukin-8 was able to discriminate between normal pancreas and chronic pancreatitis (P = .011), pancreatic cancer (P = .044), and the presence of pancreatic diseases (P = .007). Individual cytokine concentrations were not significantly different in chronic pancreatitis compared with pancreatic cancer.. Cytokine levels can be measured in pancreatic juice obtained from the duodenum without direct cannulation of the pancreatic duct. Interleukin-8 concentration in pancreatic juice can be used to discriminate between normal pancreas and patients with pancreatic disease. This is a relatively simple and noninvasive method to aid in the diagnosis of pancreatic diseases.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Biomarkers; Cytokines; Diagnosis, Differential; Endoscopy, Gastrointestinal; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lipase; Male; Middle Aged; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis, Chronic; Secretin; Transforming Growth Factor beta