Catecholamines-crafty weapons in the inflammatory arsenal of immune/inflammatory cells or opening pandora's box?

It is well established that catecholamines (CAs), which regulate immune and inflammatory responses, derive from the adrenal medulla and from presynaptic neurons. Recent studies reveal that T cells also can synthesize and release catecholamines which then can regulate T cell function. We have shown recently that macrophages and neutrophils, when stimulated, can generate and release catecholamines de novo which, then, in an autocrine/paracrine manner, regulate mediator release from these phagocytes via engagement of adrenergic receptors. Moreover, regulation of catecholamine-generating enzymes as well as degrading enzymes clearly alter the inflammatory response of phagocytes, such as the release of proinflammatory mediators. Accordingly, it appears that phagocytic cells and lymphocytes may represent a major, newly recognized source of catecholamines that regulate inflammatory responses.     

Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?

Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.     

Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases?

In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases.     

Is the endogenous peroxyl-radical scavenging capacity of plasma protective in systemic inflammatory disorders in humans?

Systemic inflammatory response syndrome (SIRS) in humans is associated with heightened intravascular oxidative stress. The clinical significance of plasma endogenous antioxidative capability in SIRS remains undetermined. Time-sequence changes of plasma total radical-trapping antioxidant parameter (TRAP) and its components were measured in 135 patients with various clinical conditions leading to SIRS. The results were correlated with clinical parameters. Plasma TRAP significantly depressed upon diagnosis of SIRS (SIRS vs. healthy subjects (n = 50), 605.7 +/- 20.4 vs. 803.4 +/- 30.8 microM Trolox equivalent, p <.001). In survivors (n = 86), TRAP declined further during the course of SIRS, followed by a mild recovery at the end of follow-up. General linear mixed model analysis revealed that uric acid, vitamin C, vitamin E and unidentified antioxidants contributed to most of the changes in TRAP (each factor p <.001). In nonsurvivors (n = 49), TRAP increased steadily until death, and the increase was predominantly the result of the increased contribution of bilirubin (p <.01). Higher TRAP levels were not correlated with diminished blood oxidants formation (r = -0.13, p.05), lower intensity of lipid peroxidation (r = 0.261, p <.05) or lesser disease severity of SIRS. The results do not support the hypothesis that the endogenous peroxyl radical scavenging ability of plasma plays a protective role in the course of SIRS.     

The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin–angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT₁) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT₁ receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.     

Effects of hesperetin on the production of inflammatory mediators in IL-1β treated human synovial cells

This study was conducted to evaluate the efficacy of hesperetin in regulating interleukin-1β (IL-1β)-induced production of the matrix metalloproteinase (MMP)-3 and IL-6 in human synovial cell line, SW982. Treatment with hesperetin at 1 or 10 μM significantly (P < 0.05) inhibited IL-1β-induced MMP-3 and IL-6 production when measured by enzyme-linked immunosorbent assay (ELISA). The effects of hesperetin on the activation of mitogen-activated protein kinases (MAPKs) were also examined in SW982 cells by ELISA assay. IL-1β-induced JNK activation was inhibited by hesperetin. These results suggest that hesperetin reduces the production of MMP and IL-6 in SW982 synovial cells by inhibiting JNK.     

Is there a role for mannan-binding lectin in the diagnosis of inflammatory bowel disease?

Mannan-binding lectin (MBL) activates the lectin-complement pathway as part of the innate immune defence by binding to the surface of microorganisms. Therefore, MBL2 presents an interesting candidate gene for the inflammatory bowel diseases, ulcerative colitis (UC) and Crohn's disease (CD). In our study, we evaluated the MBL serum concentrations and genotypes for diagnostic and classification purposes of patients with CD and UC. The MBL serum concentration was analysed in 98 CD patients and in 83 UC patients. In total, 82 patients with inflammatory rheumatic disorders and 189 healthy individuals served as controls. All study subjects were genotyped for the MBL2 polymorphisms G54D, G57E and R52C and the NOD2 (CARD15) mutations R702W, G908R and L1007fsinsC. Neither the median MBL serum concentration nor the MBL2 genotype distribution differed significantly between cohorts. Measurement of MBL serum concentrations offers no benefit for the diagnosis of CD or UC.     

Good bug, bad bug: in the case of enteric inflammatory disease does the epithelium decide?

Many studies demonstrate that intestinal inflammation is either initiated or exaggerated by a component of the normal microbiota, most likely commensal bacteria or products derived from these organisms. We review the nature of human inflammatory bowel disease, the evidence for the involvement of the normal bacterial flora in these disorders and the relevance of maintaining the integrity of the epithelial barrier. Moreover, we, and others, have shown abnormal mitochondria structure in tissue resections from patients with inflammatory bowel disease and tissues from rodents that demonstrated psychological stress-induced increases in epithelial permeability. Thus, we also consider the possibility that a defect in epithelial mitochondrial function would predispose an individual to respond to their commensal bacteria flora--no longer considering them as a beneficial passive inhabitant, but rather perceiving them as a threatening and pro-inflammatory stimulus. In support of this postulate, we discuss our recent findings from an in vitro model showing that the human colon-derived T84 cell line exposed to the metabolic stressor, dinitrophenol, and the non-pathogenic, non-invasive, Escherichia coli (strain HB101) display a loss of barrier function, increased signal transduction and increased production of the chemokine, interleukin 8.     

Effect of corticosteroids on nitric oxide production in inflammatory bowel disease: are leukocytes the site of action?

Nitric oxide (NO) production is increased in the human colonic mucosa in intestinal inflammation. We examined the effect of corticosteroids and the role of mononuclear cells in this production. Colonic biopsies from patients with ulcerative colitis and normal controls were cultured with either budesonide or prednisolone in the presence of proinflammatory cytokines. Human mixed mononuclear cells (MMCs) were cocultured with HT-29 cells stimulated with IFN-gamma and LPS in the presence or absence of corticosteroids. Nitrite production was measured in supernatants by a modification of the Griess reaction, and inducible NO synthase (iNOS) mRNA expression was studied in colonic tissue by RT-PCR. Both steroids significantly suppressed the nitrite production and iNOS mRNA expression in inflamed colonic biopsies from ulcerative colitis patients and in cytokine-stimulated normal colonic biopsies but not in cytokine-stimulated HT-29 cells. Nitrite production by HT-29 cells was significantly increased (P < 0.01) in cocultures with MMCs stimulated with IFN-gamma and LPS. The presence of either prednisolone or budesonide significantly (P < 0.01) suppressed nitrite production from cocultures of HT-29 cells and MMCs but not from cultures of HT-29 cells stimulated with conditioned media from activated MMCs. Interestingly, stimulation of HT-29 with conditioned media from MMCs pretreated with steroids before stimulation with LPS and IFN-gamma induced a significantly (P < 0.01) lower nitrite production. These results suggest that the inhibitory effect of corticosteroids on the NO production in the intestinal inflammation might be via the inhibition of MMC-produced mediators responsible for NO production by colonic epithelial cells.     

Attenuation of the cardiac inflammatory changes and lipid anomalies by (?)-epigallocatechin-gallate in cigarette smoke-exposed rats

Cigarette smoking is a major risk factor for cardiovascular diseases and exerts negative effects on the lipid profile. This study was aimed to evaluate the preventive role of (-)-epigallocatechin-gallate (EGCG) on lipid metabolism and cardiac inflammatory changes in cigarette smoke (CS) induced myocardial dysfunction. Adult male albino rats were exposed to side stream CS for a period of 12 weeks and simultaneously administered with EGCG (20 mg/kg b.w./day, p.o.). Exposure to CS showed significant increased (P < 0.05) activities of cardiac injury markers such as, creatine kinase-MB (CKMB) and lactate dehydrogenase (LDH) in serum and subsequent decrease in these enzyme activities in heart. A significant increase (P < 0.05) in serum total cholesterol, fatty acids, phospholipids, and triglycerides were observed in CS exposed rats, along with elevated low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol and decreased high density lipoprotein (HDL) cholesterol. In myocardium, total cholesterol, fatty acids and triglycerides were increased, whereas the phospholipids were found to be decreased. Cardiac lecithin: cholesterol acyl trasferase (LCAT), lipoprotein lipase (LPL), and plasma LCAT activities were significantly decreased (P < 0.05) on CS exposure. Supplementation of EGCG reverted the cardiac injury markers, abnormalities of lipid profile, and lipid-metabolizing enzymes in serum and myocardium. Western blot analysis showed a significant increase in protein expression levels of nuclear factor kappa-B (NF-κB), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) in heart of CS exposed rats. EGCG-treated rats showed a significant decrease in the expression of inflammatory markers. Our data suggest that chronic CS causes lipidemic anomalies and cardiac inflammatory aberrations which may promote cardiac dysfunction and that the antioxidant EGCG exerts a cardio protective effect via reduction of oxidative stress.     

Multi–omic analysis of signalling factors in inflammatory comorbidities

Background

Inflammation is a core element of many different, systemic and chronic diseases that usually involve an important autoimmune component. The clinical phase of inflammatory diseases is often the culmination of a long series of pathologic events that started years before. The systemic characteristics and related mechanisms could be investigated through the multi–omic comparative analysis of many inflammatory diseases. Therefore, it is important to use molecular data to study the genesis of the diseases. Here we propose a new methodology to study the relationships between inflammatory diseases and signalling molecules whose dysregulation at molecular levels could lead to systemic pathological events observed in inflammatory diseases.

Results

We first perform an exploratory analysis of gene expression data of a number of diseases that involve a strong inflammatory component. The comparison of gene expression between disease and healthy samples reveals the importance of members of gene families coding for signalling factors. Next, we focus on interested signalling gene families and a subset of inflammation related diseases with multi–omic features including both gene expression and DNA methylation. We introduce a phylogenetic–based multi–omic method to study the relationships between multi–omic features of inflammation related diseases by integrating gene expression, DNA methylation through sequence based phylogeny of the signalling gene families. The models of adaptations between gene expression and DNA methylation can be inferred from pre–estimated evolutionary relationship of a gene family. Members of the gene family whose expression or methylation levels significantly deviate from the model are considered as the potential disease associated genes.

Conclusions

Applying the methodology to four gene families (the chemokine receptor family, the TNF receptor family, the TGF– β gene family, the IL–17 gene family) in nine inflammation related diseases, we identify disease associated genes which exhibit significant dysregulation in gene expression or DNA methylation in the inflammation related diseases, which provides clues for functional associations between the diseases.

     

Assessment of the influence of the patient’s inflammatory state on the accuracy of a haptoglobin selected reaction monitoring assay

Background

The use of targeted LC-MS/MS methods for protein quantitation in clinical laboratories implies a careful evaluation of potential sources of analytical interference. In this study, we investigated whether inflammation, which is associated with both the release of proteolytic enzymes and increased expression of acute phase protease inhibitors, is affecting the accuracy of a haptoglobin selected reaction monitoring (SRM) assay.

Results

A SRM assay was developed and used to quantify haptoglobin in 57 human serum samples. The SRM assay had CVs (n = 6) of 12.9% at 698 mg/L and 11.8% at 1690 mg/L. Results of the SRM assay were compared to those of a commercial immunonephelometric test. Passing-Bablok regression gave a proportional bias of 0.92 (95% CI: 0.82 to 1.04) and a constant bias of 75.40 (95% CI: −71.09 to 251.04), indicating that SRM and immunonephelometric assays provided comparable results. We then investigated whether the accuracy of the SRM assay was influenced by the patient’s inflammatory state by assessing the relationship between the serum CRP concentration and the bias between the two methods. No correlation was found between the SRM/immunoassay bias and the CRP concentration (Pearson correlation coefficient r = 0.0898).

Conclusions

These data indicate that neither the release of proteolytic enzymes nor the increased level of protease inhibitors occurring during inflammation processes have a significant impact on the haptoglobin SRM assay accuracy. Such studies provide important information about potential sources of analytical interferences in protein SRM assays.

Electronic supplementary material

The online version of this article (doi:10.1186/1559-0275-11-38) contains supplementary material, which is available to authorized users.     

Multi-analyte profiling of inflammatory mediators in COPD sputum – The effects of processing

Prior to using a new multi-analyte platform for the detection of markers in sputum it is advisable to assess whether sputum processing, especially mucus homogenization by dithiothreitol (DTT), affects the analysis. In this study we tested a novel Human Inflammation Multi Analyte Profiling® Kit (v1.0 Luminex platform; xMAP®).Induced sputum samples of 20 patients with stable COPD (mean FEV1, 59.2% pred.) were processed in parallel using standard processing (with DTT) and a more time consuming sputum dispersion method with phosphate buffered saline (PBS) only. A panel of 47 markers was analyzed in these sputum supernatants by the xMAP®.Twenty-five of 47 analytes have been detected in COPD sputum. Interestingly, 7 markers have been detected in sputum processed with DTT only, or significantly higher levels were observed following DTT treatment (VDBP, α-2-Macroglobulin, haptoglobin, α-1-antitrypsin, VCAM-1, and fibrinogen). However, standard DTT-processing resulted in lower detectable concentrations of ferritin, TIMP-1, MCP-1, MIP-1β, ICAM-1, and complement C3. The correlation between processing methods for the different markers indicates that DTT processing does not introduce a bias by affecting individual sputum samples differently.In conclusion, our data demonstrates that the Luminex-based xMAP® panel can be used for multi-analyte profiling of COPD sputum using the routinely applied method of sputum processing with DTT. However, researchers need to be aware that the absolute concentration of selected inflammatory markers can be affected by DTT.     

Modulation of NF-κB and FOXOs by baicalein attenuates the radiation-induced inflammatory process in mouse kidney

The bioactive flavonoid baicalein has been shown to have radioprotective activity, although the molecular mechanism is poorly understood in vivo. C57BL/6 mice were irradiated with X-rays (15 Gy) with and without baicalein treatment (5 mg/kg/day). Irradiation groups showed an increase of NF-κB-mediated inflammatory factors with oxidative damage and showed inactivation of FOXO and its target genes, catalase and SOD. However, baicalein suppressed radiation-induced inflammatory response by negatively regulating NF-κB and up-regulating FOXO activation and catalase and SOD activities. Furthermore, baicalein inhibited radiation-induced phosphorylation of MAPKs and Akt, which are the upstream kinases of NF-κB and FOXOs. Based on these findings, it is concluded that baicalein has a radioprotective effect against NF-κB-mediated inflammatory response through MAPKs and the Akt pathway, which is accompanied by the protective effects on FOXO and its target genes, catalase and SOD. Thus, these findings provide new insights into the molecular mechanism underlying the radioprotective role of baicalein in mice.     

Epstein�CBarr virus-associated inflammatory pseudotumor of the spleen: report of two cases and review of the literature

We report two rare examples of Epstein–Barr virus (EBV)-associated inflammatory pseudotumor of the spleen. One patient presented with night sweats, abdominal pain, and weight loss and was found to have a splenic mass on CT scan suspected of lymphoma. The splenic mass in second patient was found incidentally at the time of work up for kidney stones. The pathologic examination of these splenectomy specimens showed similar histologic features. However, the spindle cells were composed of EBV-infected follicular dendritic cells in one case whereas the second case lacked significant follicular dendritic cell proliferation and showed only focal EBV-infected cells suggesting that these proliferations are heterogenous in nature.     

Peripheral non-viral MIDGE vector-driven delivery of β-endorphin in inflammatory pain

Background

TRPA1 has been implicated in both chemo- and mechanosensation. Recent work demonstrates that inhibiting TRPA1 function reduces mechanical hypersensitivity produced by inflammation. Furthermore, a broad range of chemical irritants require functional TRPA1 to exert their effects. In this study we use the ex-vivo skin-nerve preparation to directly determine the contribution of TRPA1 to mechanical- and chemical-evoked responses at the level of the primary afferent terminal.

Results

Acute application of HC-030031, a selective TRPA1 antagonist, inhibited all formalin responses in rat C fibers but had no effect on TRPV1 function, assessed by capsaicin responsiveness. Genetic ablation experiments corroborated the pharmacological findings as C fibers from wild type mice responded to both formalin and capsaicin, but fibers from their TRPA1-deficient littermates responded only to capsaicin. HC-030031 markedly reduced the mechanically-evoked action potential firing in rat and wild type mouse C fibers, particularly at high-intensity forces, but had no effect on the mechanical responsiveness of Aδ fiber nociceptors. Furthermore, HC-030031 had no effect on mechanically-evoked firing in C fibers from TRPA1-deficient mice, indicating that HC-030031 inhibits mechanically-evoked firing via a TRPA1-dependent mechanism.

Conclusion

Our data show that acute pharmacological blockade of TRPA1 at the cutaneous receptive field inhibits formalin-evoked activation and markedly reduces mechanically-evoked action potential firing in C fibers. Thus, functional TRPA1 at sensory afferent terminals in skin is required for their responsiveness to both noxious chemical and mechanical stimuli.     

Dietary inflammatory index and inflammatory gene interactions in relation to colorectal cancer risk in the Bellvitge colorectal cancer case–control study

Chronic inflammation is an important factor in colorectal carcinogenesis. However, evidence on the effect of pro-inflammatory and anti-inflammatory foods and nutrients is scarce. Moreover, there are few studies focusing on diet–gene interactions on inflammation and colorectal cancer (CRC). This study was designed to investigate the association between the novel dietary inflammatory index (DII) and CRC and its potential interaction with polymorphisms in inflammatory genes. Data from the Bellvitge Colorectal Cancer Study, a case–control study (424 cases with incident colorectal cancer and 401 hospital-based controls), were used. The DII score for each participant was obtained by multiplying intakes of dietary components from a validated dietary history questionnaire by literature-based dietary inflammatory weights that reflected the inflammatory potential of components. Data from four important single nucleotide polymorphisms located in genes thought to be important in inflammation-associated CRC: i.e., interleukin (IL)-4, IL-6, IL-8, and peroxisome proliferator-activated receptor-γ (PPARG) were analyzed. A direct association was observed between DII score and CRC risk (OR_{Q4 vs. Q1} 1.65, 95 % CI 1.05–2.60, and P trend 0.011). A stronger association was found with colon cancer risk (OR_{Q4 vs. Q1} 2.24, 95 % CI 1.33–3.77, and P trend 0.002) than rectal cancer risk (OR_{Q4 vs. Q1} 1.12, 95 % CI 0.61–2.06, and P trend 0.37). DII score was inversely correlated with SNP rs2243250 in IL-4 among controls, and an interaction was observed with CRC risk. Neither correlation nor interaction was detected for other inflammatory genes. Overall, high-DII diets are associated with increased risk of CRC, particularly for colon cancer, suggesting that dietary-mediated inflammation plays an important role in colorectal carcinogenesis.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-014-0447-x) contains supplementary material, which is available to authorized users.