YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients (r = 0.37, P = 0.010), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 (r = 0.36, P = 0.014), MMP-3 (r = 0.46, P = 0.001), IL-6 (r = 0.57, P < 0.001), and IL-17 (r = 0.52, P = 0.010) levels. Moreover, IL-6 and IL-17 enhanced YKL-40 production in human primary chondrocyte cultures. The present study introduces YKL-40 as a cartilage-derived factor associated with mediators of inflammation and cartilage destruction involved in the pathogenesis of OA.
Objective: To investigate the endogenous regulation of interleukin‐1 (IL‐1) cytokine network in osteoarthritic (OA) and rheumatoid (RA) cartilage in relation to nitric oxide (NO) production.Methods: Cartilage specimen obtained from OA and RA patients undergoing knee replacement surgery were studied for iNOS expression, NO and IL‐1 antagonist production in tissue culture.Results: OA cartilage responded to IL‐1β ‐stimulation with higher NO production than RA cartilage, whereas there was no difference in NO synthesis between OA and RA samples when stimulated by TNFα or LPS. Interleukin‐1 receptor antagonist (IL‐1Ra) production was higher in RA cartilage than in OA cartilage, and its production was increased by NO synthase inhibitor 1400W.Conclusion: IL‐1β is a potent stimulator of NO production by the iNOS pathway in RA and more pronouncedly in OA cartilage. This process is regulated by cartilage derived IL‐1 antagonists, and is implicated in cartilage destruction and synovial inflammation in OA and RA joints.
Transient receptor potential ankyrin 1 (TRPA1) is an ion channel mainly studied in sensory neurons where it mediates itch, pain and neurogenic inflammation. Recently, some nonneuronal cells have also been shown to express TRPA1 to support inflammatory responses. To address the role of TRPA1 in skin inflammation, we aimed to investigate TRPA1 expression in keratinocytes. HaCaT cells (a model of human keratinocytes) and skin biopses from wild-type and TRPA1 deficient mice were used in the studies. TRPA1 expression in nonstimulated keratinocytes was very low but significantly inducible by the proinflammatory cytokine tumor necrosis factor (TNF) in an nuclear factor kappa B (NF-κB), and mitogen-activated protein (MAP) kinase (p38 and c-Jun N-terminal kinase, JNK)-dependent manner. Interestingly, drugs widely used to treat skin inflammation, the calcineurin inhibitors tacrolimus and cyclosporine and the glucocorticoid dexamethasone, significantly decreased TRPA1 expression. Furthermore, pharmacological inhibition and genetic deletion of TRPA1 reduced the synthesis of TNF-induced monocyte chemoattractant protein 1 (MCP-1) in keratinocytes and mouse skin biopsies. In conclusion, these findings point to an inflammatory role for TRPA1 in keratinocytes and present TRPA1 as a potential drug target in inflammatory skin diseases.
Background and purpose: Levosimendan is used in the treatment of decompensated heart failure. It increases the contractility of the myocardium by sensitizing troponin C to calcium. In addition, levosimendan has been reported to have beneficial effects in experimental models of septic shock. Because heart failure and sepsis have been associated with excessive nitric oxide (NO) production through inducible NOS (iNOS), we investigated the effects of the simendans on NO production and iNOS expression and on generation of pro‐inflammatory cytokines. Experimental approach: Macrophages and fibroblasts were exposed to inflammatory stimuli to induce iNOS expression. Proteins were measured by western blot and mRNA expression was determined by quantitative RT‐PCR. Promoter activity and nuclear factor‐κB (NF‐κB) and the γ‐activated site (GAS; binding site for signal transducer and activator of transcription 1; STAT1)‐mediated transcription were investigated using luciferase reporter constructs. Cytokines tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured by ELISA. Key results: Levosimendan and dextrosimendan decreased NO production in a dose‐dependent manner in cells exposed to inflammatory stimuli. The simendans decreased iNOS protein and mRNA expression but did not affect iNOS mRNA decay. These compounds decreased iNOS promoter activity and inhibited NF‐κB‐mediated transcription but not that mediated by STAT1/GAS. The simendans reduced IL‐6 production slightly but they had no effect on TNF‐α synthesis. Conclusions and implications: The simendans downregulated NF‐κB‐dependent transcription and decreased iNOS promoter activity, iNOS expression and NO production. These mechanisms may contribute to their beneficial clinical effects. British Journal of Pharmacology (2008) 155 , 884–895; doi: 10.1038/bjp.2008.328 ; published online 18 August 2008
Abstract Objective Changes in the tumor necrosis factor‐α ( TNF α) have been associated with major depressive disorder ( MDD ). Findings concerning the effects of electroconvulsive therapy ( ECT ) on the TNF α level have been contradictory. The aim was to examine the immediate and long‐term changes in the TNF α level and their associations with symptom reduction in patients with MDD during ECT . Method The study included 30 patients with MDD . Their TNF α levels were measured at baseline and 2 and 4 hr after the first, fifth and last ECT session. Depressive symptoms were assessed with the Montgomery‐Asberg Depression Rating Scale ( MADRS ). Results The TNF α level decreased from baseline to the 2‐ and 4‐hr measurements. There was a correlation between the first ECT session TNF α levels and the relative symptom reduction according to the MADRS score after the ECT series. Both the first (baseline) ECT and 4‐hr TNF α levels were lower in responders than in nonresponders. Conclusion ECT consistently induced a decrease in the TNF α level after each studied session. A low TNF α level at the first ECT appeared to predict a symptom reduction. These findings suggest that TNF α might have a role in the pathogenesis in MDD and in the mechanism of action of ECT .
Abstract Background Dysbiotic intestinal and oral microbiota have been implicated in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms how microbiota could impact disease activity have remained elusive. The aim of this study was to assess the association of the biological activity of serum lipopolysaccharides (LPS) with disease activity and likelihood of achieving remission in RA patients. Methods We measured Toll-like receptor (TLR) 4-stimulating activity of sera of 58 RA patients with a reporter cell line engineered to produce secreted alkaline phosphatase in response to TLR4 stimulation. Levels of LPS-binding protein, CD14, and CD163 were determined by ELISA assays. Results The patient serum-induced TLR4 activation (biological activity of LPS) was significantly associated with inflammatory parameters and body mass index at baseline and at 12 months and with disease activity (DAS28-CRP, p <0.001) at 12 months. Importantly, baseline LPS bioactivity correlated with disease activity ( p =0.031) and, in 28 early RA patients, the likelihood of achieving remission at 12 months ( p =0.009). The level of LPS bioactivity was similar at baseline and 12-month visits, suggesting that LPS bioactivity is an independent patient-related factor. Neutralization of LPS in serum by polymyxin B abrogated the TLR4 signaling, suggesting that LPS was the major contributor to TLR4 activation. Conclusion We describe a novel approach to study the biological activity of serum LPS and their impact in diseases. The results suggest that LPS contribute to the inflammatory burden and disease activity on patients with RA and that serum-induced TLR4 activation assays can serve as an independent prognostic factor. Graphical Abstract A graphical summary of the conclusions of the study.
Orazipone [OR-1384; 3-[4-(methylsulfonyl)benzylidene]pentane-2,4-dione] is a novel sulfhydryl-modulating compound that has anti-inflammatory properties in experimental models of asthma and inflammatory bowel disease. In inflammation, inducible nitricoxide synthase (iNOS) generates NO, which modulates the immune response. Compounds that inhibit iNOS expression or iNOS activity possess anti-inflammatory effects. In the present study, we examined the effects of orazipone and its derivative OR-1958 [3-[3-chlorine-4-(methylsulfonyl)benzylidene]pentane-2,4-dione] on iNOS expression and NO production in J774 macrophages stimulated by bacterial lipopolysaccharide (LPS) and in human alveolar epithelial cells activated by proinflammatory cytokines. Protein expression and nuclear translocation of transcription factors were measured by Western blot. iNOS mRNA expression was determined by quantitative reverse transcription-polymerase chain reaction and iNOS mRNA stability by actinomycin D assay. iNOS promoter activity was studied in a cell line expressing luciferase under the control of iNOS promoter. Orazipone and its derivative OR-1958 but not its nonthiol-modulating analog inhibited iNOS expression and NO production in a concentration-dependent manner. Orazipone decreased LPS-induced iNOS mRNA expression, but the decay of iNOS mRNA was not affected. Orazipone extensively prevented LPS-induced activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription (STAT) 1, which are important transcription factors for iNOS. In agreement, human iNOS promoter activity was inhibited by orazipone. In conclusion, orazipone decreased activation of inflammatory transcription factors NF-κB and STAT1, and expression of iNOS in cells exposed to inflammatory stimuli. The thiolmodulating property seems to be critical in mediating the antiinflammatory effects of orazipone.
Objectives: Fibroblast growth factor (FGF)-2 is a member of the FGF family and is found in the synovial fluid of patients with osteoarthritis (OA). The aim of this study was to investigate the effects of FGF-2 on human OA cartilage/chondrocytes by examining the association between FGF-2 and the cartilage degrading enzymes matrix metalloproteinase (MMP)-1 and MMP-13 and the major cartilage matrix components aggrecan and collagen II.
Metabolic syndrome and related cardiovascular risk factors are well-known comorbidities among patients with schizophrenia. Biomarkers of these antipsychotic-associated metabolic adverse effects and antipsychotic-induced weight gain are needed. Glucagon-like peptide-1 (GLP-1) is involved in insulin secretion, regulation of satiety, inhibition of food intake, and inhibition of gastric emptying. GLP-1 also induces reduction in body weight. Visfatin/ NAMPT/ PBEF is an adipocytokine secreted by several cells and tissues. Increased plasma visfatin levels have been associated with overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases, low grade inflammation, and proinflammatory markers. Associations between antipsychotic-induced weight gain and serum visfatin and GLP-1 levels have been little studied in patients with schizophrenia. The aim of the present study was to test the possible role of serum GLP-1 and visfatin level alterations as markers of weight gain in association with metabolic and inflammatory markers in 190 patients (109 male, 81 female) with schizophrenia on clozapine treatment. High serum levels of GLP-1 correlated significantly with higher levels of visfatin, leptin, insulin, HOMA-IR, higher BMI, and weight change among men. Associations between serum visfatin levels and BMI or weight change were not found in the present patients. Serum GLP-1 level seems to be a marker of metabolic risk factors among men with schizophrenia on clozapine treatment. Female patients may be more sensitive to suppressive effects of clozapine on GLP-1 secretion. Patients on clozapine would benefit from GLP-1 agonists as preventive treatment.
