interleukin-8 and Familial-Mediterranean-Fever

Topics: Apoptosis; Chediak-Higashi Syndrome; Familial Mediterranean Fever; Humans; Inflammation; Interleukin-1; Interleukin-8; Leukocyte-Adhesion Deficiency Syndrome; Neutropenia; Neutrophil Activation; Neutrophils; Phagocytosis

Familial Mediterranean fever (FMF) is a disease of unknown etiology characterized by recurrent attacks of polyserositis (peritonitis, pleuritis, and arthritis) and fever. We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 8 (IL-8), which are important mediators in leukocyte-endothelial adhesion and leukocyte accumulation in tissues.. sICAM-1 and IL-8 levels were studied in 30 patients with FMF during attacks and remission, along with 23 healthy and 26 disease controls. sICAM-1 and IL-8 levels were measured with commercial ELISA systems.. Median levels of sICAM-1 were significantly elevated in patients with FMF during attacks (FMF-a) and remission periods (FMF-r) compared to healthy controls (HC) (FMF-a: 600 ng/ml, FMF-r: 520 ng/ml, HC: 353 ng/ml; FMF-a vs. HC: p<0.0001, FMF-r vs. HC: p = 0.002). IL-8 levels were also significantly elevated in FMF-a compared to HC (37 vs. 25 pg/ml; p = 0.009), but not during remission (26 pg/ml; p = 0.7). A significant correlation was observed between sICAM-1 and IL-8 levels (r = 0.33, p = 0.01). sICAM-1 levels also correlated significantly with erythrocyte sedimentation rate, C-reactive protein, and fibrinogen levels of patients with FMF.. Increased levels of sICAM-1 and IL-8 in FMF suggest that neutrophils are active with increased adhesion in FMF. Since increased levels of sICAM-1 are also observed during remission, subclinical disease activity and inflammation seem to be present in some patients.

Topics: Acute Disease; Adolescent; Adult; Arthritis, Juvenile; Child; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Familial Mediterranean Fever; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Prognosis; Sensitivity and Specificity; Severity of Illness Index

Familial Mediterranean fever (FMF) and systemic juvenile idiopathic arthritis (sJIA) are chronic inflammatory diseases and anti-inflammatory agents are used in their treatment. This study evaluates the periodontal status and cytokine response in pediatric patients with FMF or sJIA.. Forty-eight FMF/sJIA patients were under treatment/control and in attack-free period; 20 systemically healthy children participated in the study. FMF/sJIA patients were divided into two subgroups based on the treatment they received: receiving anti-IL-1 therapy (anti-IL-1 ( +)) and not receiving anti-IL-1 therapy (anti-IL-1 ( -)). The clinical periodontal indices were recorded. Gingival crevicular fluid (GCF) and serum samples were collected. Cytokine levels (IL-1β, IL-1α, TNF-α, IL-6, IL-8, IL-10, IL-17, IL-33) in GCF and serum were measured using ELISA kits.. There was no significant difference between the groups in terms of GCF IL-1β and IL-1α levels although, BoP and GI were significantly lower in the anti-IL-1 ( +) group compared to the control group. GCF IL-10 level was higher in the anti-IL-1 ( -) group than in the control group; GCF IL-8 levels were lower in both FMF/sJIA subgroups versus controls. There was no significant difference between serum cytokine levels of FMF/sJIA subgroups.. Considering the significant decrease in GI, BoP, and GCF IL-8 levels in the anti-IL-1 ( +) group, it can be concluded that anti-IL-1 medications may suppress periodontal inflammation clinically and immunologically.. Anti-IL agents are not currently used in periodontal therapy. However, this study demonstrated the positive effect of anti-IL-1 medications on periodontal inflammation in pediatric patients with FMF or sJIA.

Topics: Arthritis, Juvenile; Child; Familial Mediterranean Fever; Gingival Crevicular Fluid; Humans; Inflammation; Interleukin-10; Interleukin-8

Familial Mediterranean fever (FMF) is a recessive inherited autoinflammatory syndrome. Patients with FMF have symptoms such as recurrent fever and abdominal pain, sometimes accompanied by arthralgia. Biopsy specimens have revealed substantial neutrophil infiltration into synovia. FMF patients have a mutation in the Mediterranean fever gene, encoding pyrin, which is known to regulate the inflammasome, a platform for processing interleukin (IL)-1β. FMF patients heterozygous for E148Q mutation, heterozygous for M694I mutation, or combined heterozygous for E148Q and M694I mutations, which were found to be major mutations in an FMF study group in Japan, suffer from arthritis, the severity of which is likely to be lower than in FMF patients with M694V mutations. Expression plasmids of wild-type (WT) pyrin and mutated pyrin, such as E148Q, M694I, M694V, and E148Q+M694I, were constructed, and SW982 synovial sarcoma cells were transfected with these expression plasmids. IL-8 and IL-6 were spontaneously secreted from the culture supernatant of SW982 cells without any stimulation, whereas IL-1β and TNF-α could not be detected even when stimulated with lipopolysaccharide. Notably, two inflammasome components, ASC and caspase-1, could not be detected in SW982 cells by Western blotting. IL-8 but not IL-6 secretion from SW982 cells was largely suppressed by WT pyrin, but less suppressed by mutated pyrin, which appeared to become weaker in the order of E148Q, M694I, E148Q+M694I, and M694V mutations. As for IL-8 and IL-6, similar results were obtained using stable THP-1 cells expressing the WT pyrin or mutated pyrins, such as M694V or E148Q, when stimulated by LPS. In addition, IL-8 secretion from mononuclear cells of FMF patients was significantly higher than that of healthy volunteers when incubated on a culture plate. Thus, our results suggest that IL-8 secretion from SW982 synovial sarcoma cells suppressed by pyrin independently of inflammasome is affected by pyrin mutations, which may reflect the activity in FMF arthritis.

Topics: CARD Signaling Adaptor Proteins; Caspase 1; Cell Line, Tumor; Cytokines; Cytoskeletal Proteins; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Familial Mediterranean Fever; Genetic Association Studies; HEK293 Cells; Humans; Inflammasomes; Interleukin-8; Leukocytes, Mononuclear; Mutation, Missense; Phosphorylation; Protein Processing, Post-Translational; Pyrin; Sarcoma, Synovial; Solubility

Familial Mediterranean fever (FMF) is autoinflammatory disorder, characterized by MEFV gene mutations and recurrent episodes of fever and serosal or synovial inflammation. Neutrophils are the predominant effector cells of acute inflammatory attacks in FMF; however pathogenic role and molecular phenotype of these cells remain largely unknown. To gain insight into the processes that contribute to the self-directed autoinflammation we characterized expression of a spectrum of genes involved in regulation of inflammation in unstimulated and LPS-activated neutrophils from FMF patients. Expression of 12 candidate immune genes encoding for inflammation-related molecules was assessed by quantitative RT-PCR in freshly isolated and LPS-stimulated peripheral polymorphonuclear neutrophils from fifteen FMF patients in attack-free period and ten healthy volunteers as controls. The relative expression was calculated using the second derivative method; the target gene expression was normalized to the expression of RPL32 gene. FMF neutrophils were characterized by up-regulated baseline gene expression of c-FOS (9.5-fold, p < 0.05), IL-8 (12-fold, p < 0.05), MMP9 (8-fold, p < 0.01), TLR2 (7-fold, p < 0.05) compared to the neutrophils from control subjects, a trend was also evident towards increased caspase-1 expression (3-fold, p = 0.09). Discriminant analysis clustered the patient and control subjects into two distinct groups (Wilks's lambda = 0.165, p = 0.042). Further, LPS-induced alterations of expression profiles were shared between FMF and healthy neutrophils, the profile consisting namely of up-regulated IL-1β, TLR4, IL-8, and TNFAIP6 transcripts. Present study demonstrates distinct expression patterns of pre-activated neutrophils during attack-free period of FMF when compared to neutrophils from healthy controls. Furthermore, our data emphasize the importance of host-derived ligands in activation of FMF neutrophils.

Topics: Adolescent; Adult; Cell Adhesion Molecules; Cluster Analysis; Familial Mediterranean Fever; Female; Gene Expression Profiling; Genetic Predisposition to Disease; Humans; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Male; Neutrophils; Phenotype; Principal Component Analysis; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 4; Up-Regulation; Young Adult

The aim of the present study was to determine synovial levels of ELR (+) CXC chemokines, known to attract mainly neutrophils to inflamed tissues by binding the neutrophil chemokine receptors CXCR1 and CXCR2 and promoting neovascularization in patients with various inflammatory disorders. The study group consisted of 14 patients with Behçet's disease and nine with familial Mediterranean fever. Fourteen patients with rheumatoid arthritis and 16 with osteoarthritis served as controls. Synovial chemokine levels were measured by two-step sandwich enzyme-linked immunosorbent assay, and significant differences were found in the various chemokines studied. In addition to its angiogenic properties, increased synovial levels of interleukin-8 by attraction of more neutrophils to synovial fluids might also be responsible for the acute synovitis in patients with Behçet's disease. However, the absence of chronic changes with the eventual development of pannus and erosions might result from relatively lower expression of interleukin-8 and the transient, short-lived nature of the arthritis observed in these patients.

Topics: Adult; Angiogenesis Inhibitors; Arthritis, Rheumatoid; Behcet Syndrome; Chemokine CXCL1; Chemokine CXCL5; Chemokines, CXC; Familial Mediterranean Fever; Female; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Male; Microtubule-Associated Proteins; Middle Aged; Neovascularization, Pathologic; Osteoarthritis, Knee; Synovial Fluid

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and articular syndrome is an autoinflammatory disease characterized by urticarial rash, arthropathy, and central nervous system inflammation.. To describe a 13-year-old girl with overlapping symptoms of NOMID and Muckle-Wells syndrome who has a mutation in cryopyrin (NALP3).. We examined neutrophil migration using transwell assay and time-lapse videomicroscopy. We also examined p38 mitogen-activated protein kinase (MAPK) activation in patient and control neutrophils using Western blot analysis.. Neutrophil defects in chemotactic migration were found to a variety of chemoattractants, including interleukin 8, N-formyl-methionyl-leucyl-phenylalanine, complement C5a, and leukotriene B4. Her neutrophils exhibited elevated basal and stimulated p38 MAPK activation in response to interleukin 8, N-formyl-methionyl-leucyl-phenylalanine, complement C5a, and leukotriene B4.. This study is the first, to our knowledge, to demonstrate defects in neutrophil chemotaxis and p38 MAPK signaling in a patient with NOMID and Muckle-Wells syndrome and a cryopyrin mutation.

Topics: Adolescent; Carrier Proteins; Chemotaxis, Leukocyte; Complement C5a; Familial Mediterranean Fever; Female; Humans; Inflammation; Interleukin-8; Leukotriene B4; Mutation; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein; p38 Mitogen-Activated Protein Kinases

Familial Mediterranean fever (FMF) is a recessively inherited inflammatory disorder, characterized by recurrent attacks of fever and serositis. Screening of mutations in the causing gene (MEFV) now allows accurate diagnosis of FMF among other inflammatory conditions. It is well documented that secreted levels of some pro-inflammatory cytokines are elevated in FMF. Here, we investigated cytokine expression at the transcriptional level, in patients that could be genetically ascertained. We have measured the transcript abundance of tumor necrosis factor alpha, interleukin-1beta, interleukin-6 and interleukin-8, in circulating leukocytes and shown that these were more elevated in attack-free FMF patients than in controls (P=0.01, P=0.008, P=0.02, P=0.001 respectively). There was no significant difference according to MEFV genotype or colchicine treatment. Our results suggest that cytokine transcriptional pathways are misregulated in attack-free FMF patients, and further supports the hypothesis that these patients have subclinical inflammation between attacks.

Topics: Colchicine; Cytokines; Cytoskeletal Proteins; Familial Mediterranean Fever; Genotype; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Proteins; Pyrin; RNA, Messenger; Transcriptional Activation; Tumor Necrosis Factor-alpha

Familial Mediterranean fever (FMF) is an inherited disease whose manifestations are acute but reversible attacks of sterile inflammation affecting synovial and serosal spaces. The FMF gene (MEFV) was recently cloned, and it codes for a protein (pyrin/marenostrin) homologous to known nuclear factors. We previously reported the deficient activity of a C5a/interleukin (IL)-8 inhibitor, a physiologic regulator of inflammatory processes, in FMF serosal and synovial fluids. We now describe the concomitant expression of MEFV and C5a/IL-8-inhibitor activity in primary cultures of human fibroblasts. Fibroblasts grown from synovial and peritoneal tissues displayed C5a/IL-8-inhibitor activity that could be further induced with phorbol myristate acetate (PMA) and IL-1 beta. Very low levels of chemotactic inhibitor were evident in skin fibroblast cultures or in peritoneal and skin fibroblasts obtained from FMF patients. MEFV was expressed in peritoneal and skin fibroblasts at a lower level than in neutrophils and could be further induced by PMA and IL-1 beta. In the FMF cultures, the MEFV transcript carried the M694V mutation, consistent with the genetic defect found in patients with this disease. MEFV was also expressed in other cell lines that do not produce C5a/IL-8 inhibitor. These findings suggest that human primary fibroblast cultures express MEFV and produce C5a/IL-8-inhibitor activity. The interrelationship between pyrin, the MEFV product, and the C5a/IL-8 inhibitor requires further investigation. (Blood. 2000;96:727-731)

Topics: Cells, Cultured; Complement C5a; Complement Inactivator Proteins; Cytoskeletal Proteins; Familial Mediterranean Fever; Fibroblasts; Gene Expression; Humans; Interleukin-1; Interleukin-8; Peritoneum; Proteins; Pyrin; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane; Tetradecanoylphorbol Acetate

The etiopathogenesis of Behçet's disease (BD) has not yet been clarified but might involve immune dysfunction. As cytokines are involved in the regulation of immune responses and inflammatory reactions, we investigated whether they may play a role in the pathogenesis of BD.. We investigated spontaneous and lipopolysaccharide (LPS) stimulated production of tumor necrosis factor alpha (TNF alpha), interleukin (IL) 1, IL-6, IL-8 and granulocyte monocyte macrophage colony stimulating factor (GM-CSF) by peripheral blood monocytes from 21 patients with BD, 10 healthy controls and 10 patients with familial Mediterranean fever (FMF), another chronic inflammatory disease. We also studied superoxide generation and surface antigen expression by polymorphonuclear neutrophils (PMN).. The spontaneous secretion of TNF alpha, IL-6 and IL-8 by monocytes was significantly increased in patients with active BD. The secretion of TNF alpha, IL-1, IL-6 and IL-8 was found to be in normal range in asymptomatic patients with FMF. The LPS stimulated production of TNF alpha, IL-6, IL-1 and IL-8 was significantly increased in patients with BD, without any correlation with BD activity. In vitro, PMN spontaneously generated significant amounts of superoxide in patients with active BD.. Taken together, our results suggest that monocyte and PMN dysfunctions may play a role in the pathogenesis of BD.

Topics: Adult; Behcet Syndrome; Complement System Proteins; Cytokines; Familial Mediterranean Fever; Female; Humans; Immunoglobulins; Interleukin-6; Interleukin-8; Male; Middle Aged; Monocytes; Neutrophils; Reference Values; Superoxides; Tumor Necrosis Factor-alpha

Synovial fluids from patients with osteoarthritis contain a chemotactic inhibitor that acts by antagonizing the complement-derived chemotactic anaphylotoxin, C5a. The activity of this inhibitor in synovial fluids from patients with several forms of inflammatory arthritis (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and gout) were comparable to the activity present in osteoarthritic synovial fluids. In contrast, levels of inhibitory activity in synovial fluids from 9 patients with familial Mediterranean fever were decreased to less than 20% of those found in osteoarthritis fluids. The possibility was considered that the diminished inhibitory activity in fluids from patients with familial Mediterranean fever plays a part in the pathogenesis of the inflammatory attacks characteristic of this disease.

Topics: Adult; Chemotactic Factors; Familial Mediterranean Fever; Female; Humans; Interleukin-8; Leukocyte Count; Lymphokines; Male; Middle Aged; Osteoarthritis; Synovial Fluid