Case Report: Analysis of Inflammatory Cytokines IL-6, CCL2/MCP1, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP10 in a Cystic Fibrosis Patient Cohort During the First Wave of the COVID-19 Pandemic.
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ABSTRACT:
SUBMITTER: Baresi G
PROVIDER: S-EPMC8291286 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Patients with temporomandibular joint disorders (TMD), reactive arthritis and rheumatoid arthritis often have combined etiology of hereditary and microenvironmental factors contributing to joint pain. Multiple clinical and animal studies indicate 'double-hit' inflammatory insults can cause chronic inflammation. The first inflammatory insult primes the immune system and subsequent insults elicit amplified responses. The present 'double hit' study produced a chronic orofacial pain model in mice with genetic deletion of both TNF? receptors (TNFR1/R2-/-), investigating the main nociceptive signalling pathways in comparisons to wild type mice.An initial inflammatory insult was given unilaterally into the temporomandibular joint (TMJ). Secondary hypersensitivity was tested on the skin over the TMJ throughout the experiment. Three weeks later after complete reversal of hypersensitivity, a second inflammatory insult was imposed on the colon. Pharmacological interventions were tested for efficacy after week 10 when hypersensitivity was chronic in TNFR1/R2-/- mice. Serum cytokines were analysed at Days 1, 14, and Week 18.The double hit insult produced chronic hypersensitivity continuing through the 4-month experimental timeline in the absence of TNF? signalling. P2X7 and NMDA receptor antagonists temporarily attenuated chronic hypersensitivity. Serum cytokine/chemokine analysis on Day 14 when CFA induced hypersensitivity was resolved identified increased levels of pro-inflammatory cytokines CCL2, CXCL9, CXCL10, RANTES and decreased levels of anti-inflammatory cytokines IL-1ra and IL-4 in TNFR1/R2-/- compared to WT mice.These data suggest a causal feed-forward signalling cascade of these little studied cytokines have the potential to cause recrudescence in this orofacial inflammatory pain model in the absence of TNF? signalling.Using a mouse model of chronic inflammatory temporomandibular joint disorder, we determined that absence of functional TNFR1/R2 induces aberrant inflammatory signalling caused by other increased pro-inflammatory and decreased anti-inflammatory cytokines that could serve as blood biomarkers and may predict disease progression.
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Project description:In cystic fibrosis (CF), colonization of the airways with Pseudomonas aeruginosa is associated with disease deterioration. The mechanism behind the disease progression is not fully understood. The present work shows that the antibacterial chemokine MIG/CXCL9 is present in the airways and in sputum of CF patients. MIG/CXCL9 showed high bactericidal activity against. P. aeruginosa, including some strains from the airways of CF patients. Full-length MIG/CXCL9 was detected in sputum from healthy controls and CF patients colonized with P. aeruginosa. However, degraded MIG/CXCL9 was only found in CF sputum. In vitro, elastase of P. aeruginosa cleaved off a fragment of similar size and two additional fragments from MIG/CXCL9. The fragments showed less bactericidal activity against P. aeruginosa compared with the full-length protein. The fragments did not activate the MIG/CXCL9 receptor CXCR3 (expressed e.g. by NK cells, mast cells, and activated T cells) but instead displayed noncompetitive inhibition. In vitro, a decrease in CXCR3-bearing cells was found within and in the proximity of the bronchial epithelium of CF lung tissue compared with controls. Taken together, both bactericidal and cell-recruiting activities of MIG/CXCL9 are corrupted by P. aeruginosa through release of elastase, and this may contribute to impaired airway host defense in CF.
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Project description:The pathogenesis of the immunoglobulin A vasculitis (IgAV) is still unknown. The available data shows that interleukin (IL)-17, IL-18, IL-23, regulated on activation, normal T cell expressed and secreted (CCL 5, RANTES), and interferon (IFN)-?-inducible protein 10 (IP10) participate in the pathogenesis of IgAV by influencing the recruitment of leukocytes to the site of inflammation. The aim of this study was to analyze the serum concentration of IL-17A, IL-18, IL-23, RANTES, and IP10 in patients with acute IgAV compared to healthy children. Moreover, we wanted to assess the suitability of the levels of tested cytokines to predict the severity of the disease. All children with IgAV hospitalized in our institution between 2012 and 2017 were included in the study. Cytokines levels were determined in a serum sample secured at admission to the hospital. Basic laboratory tests have also been analyzed. IL-17A, IL-18, and IL-23 were significantly higher in whole IgAV group (52.25 pg/ml; 164.1 pg/ml and 700 pg/ml, respectively) than in the control group (27.92 pg/ml; 140.1 pg/ml and 581.5 pg/ml, respectively). The receiver operating characteristic (ROC) curve analysis revealed the largest area under the curve (AUC 0.979, p?<?0.001) for the IL-17A with 95.1% sensitivity and 91.7% specificity. There were no significant differences in cytokine levels depending on the severity of the IgAV. Although the serum levels of the IL-17A, IL-18, and IL-23 increase significantly in the acute phase of the IgAV, they cannot be used as indicators of predicting the course of the disease. IL-17A seems to be a good predictor of IgAV occurrences.
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Project description:Coronary artery inflammation is a critical process in the pathogenesis of myocardial infarction (MI). The chemokine CCL5/RANTES (regulated upon activation, normal T cells expressed and secreted) is expressed in advanced atherosclerotic lesions. Functional polymorphisms of the RANTES gene can, therefore, be involved in the pathogenesis of coronary artery disease. We examined the association of polymorphisms in the RANTES gene with myocardial infarction in Slavonic populations of Czech and Russian origin. A total of 467 post-MI patients and 337 control subjects were genotyped for RANTES promoter G-403A (rs2107538) and intron 1.1?T/C (rs2280789) variants by PCR-SSP. Both RANTES genotypes and allele frequencies did not differ between case and control groups. Haplotype-based analysis also failed to reveal an association between MI and investigated markers. Strong linkage disequilibrium was detected between particular RANTES alleles. The data do not support an association between RANTES G-403A polymorphism and MI, as reported previously.
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Project description:ObjectivesThe main histological change in rheumatoid arthritis (RA) is the villous proliferation of synovial lining cells, an important source of cytokines and chemokines, which are associated with inflammation. The aim of this study was to evaluate gene expression in the microdissected synovial lining cells of RA patients, using those of osteoarthritis (OA) patients as the control.MethodsSamples were obtained during total joint replacement from 11 RA and five OA patients. Total RNA from the synovial lining cells was derived from selected specimens by laser microdissection (LMD) for subsequent cDNA microarray analysis. In addition, the expression of significant genes was confirmed immunohistochemically.ResultsThe 14 519 genes detected by cDNA microarray were used to compare gene expression levels in synovial lining cells from RA with those from OA patients. Cluster analysis indicated that RA cells, including low- and high-expression subgroups, and OA cells were stored in two main clusters. The molecular activity of RA was statistically consistent with its clinical and histological activity. Expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF1), and the chemokines CXCL9, CXCL10, and CCL5 were statistically significantly higher in the synovium of RA than in that of OA. Immunohistochemically, the lining synovium of RA, but not that of OA, clearly expressed STAT1, IRF1, and chemokines, as was seen in microarray analysis combined with LMD.ConclusionsOur findings indicate an important role for lining synovial cells in the inflammatory and proliferative processes of RA. Further understanding of the local signalling in structural components is important in rheumatology.
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Project description:Chemokines are instrumental in macrophage- and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas(lpr) mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2-/- and wild-type (WT) MRL-Fas(lpr) kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10-/- MRL-Fas(lpr) mice, and CXCL10-/- C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3-/- , CXCL9-/- , and CXCL10-/- B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3-/- and CXCL9-/- mice but not in CXCL10-/- mice. With nephrotoxic serum nephritis, CXCR3-/- and CXCL9-/- mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9
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Project description:Recently, we identified a lung adenocarcinoma signature that segregated tumors into three clades distinguished by histological invasiveness. Among the genes differentially expressed was the type II transforming growth factor-beta receptor (TGFbetaRII), which was lower in adenocarcinoma mixed subtype and solid invasive subtype tumors compared with bronchioloalveolar carcinoma. We used a tumor cell invasion system to identify the chemokine CCL5 (RANTES, regulated on activation, normal T-cell expressed and presumably secreted) as a potential downstream mediator of TGF-beta signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFbetaRII-repressed cells. We examined invasion in TGFbetaRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFbetaRII knockdown. In addition, we examined the clinical relevance of the RANTES-CCR5 pathway by establishing an association of RANTES and CCR5 immunostaining with invasion and outcome in human lung adenocarcinoma specimens. Moderate or high expression of both RANTES and CCR5 was associated with an increased risk for death, P=0.014 and 0.002, respectively. In conclusion, our studies indicate RANTES signaling is required for invasion in TGFbetaRII-deficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.
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