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PubMed1999

Induction of macrophage inflammatory protein-1alpha and vascular endothelial growth factor during inflammatory neovascularization in the mouse cornea.

We predicted that the appearance of macrophages in inflammatory areas is necessary for angiogenic responses in various inflammatory diseases. Using a mouse inflammatory corneal model in which model mouse corneas were cauterized with silver nitrate, we examined the infiltration of macrophages immunohistochemically and the total area of neovascularization quantitively. The expression of macrophage inflammatory protein-1alpha (MIP-1alpha) and vascular endothelial growth factor (VEGF) levels were also examined. A day after cauterization, short capillaries began to develop into the corneal stroma, and after 4 or 5 days the neovascularization became maximal and then began to regress. The number of macrophages within the cauterized cornea increased to a maximum at day 3 and began to decrease at day 5. The number of infiltrated macrophages reached maximum at day 3. Both MIP-1alpha and VEGF protein levels increased markedly immediately after the chemical cauterization, and production of MIP-1alpha (85.8 pg/4 corneas) and VEGF (206.5 pg/4 corneas) was maximal at 1 day and 0.5 day after cauterization, respectively. MIP-1alpha and VEGF mRNA levels also increased at 0.5 day after cauterization. In situ hybridization showed that MIP-1alpha was localized in corneal epithelial cells, and VEGF was localized in corneal epithelial cells and infiltrating inflammatory cells. MIP-1alpha and VEGF may have an important role in recruiting macrophages and neovascularization.

Journal Article↗

PubMed1982

Elevation of serum chemotactic factor inactivator activity in rabbits induced by inflammation and chemotactic factor.

Inflammatory mediators such as the vasoactive and chemotactic factors, which are formed during the activation of serum complement, are extremely potent biologic peptides and are thought to be under the rigid control of specific serum-derived regulators or inactivators, including the anaphylatoxin inactivator (AI) and the chemotactic factor inactivator (CFI). Our understanding of the biologic importance and implication of these regulators in inflammatory reactions is primarily based on in vitro observations, and there is only limited data on their in vivo importance. Previously, alterations in CFI and AI levels were detected in chronic inflammatory disease states, but no data on their activity or role during acute inflammatory reactions have been demonstrated. Here we demonstrate the elevation of serum CFI activity during acute inflammatory reactions in rabbits. Specifically, inflammatory reactions were induced in rabbits by intraperitoneal injections of 0.1% oyster glycogen. Rabbit serum CFI levels rose rapidly over the first 4 hours after glycogen injection, reaching levels 4-8 times higher than the preglycogen serum CFI levels. Additional studies demonstrated that acute elevations of serum CFI levels could also be induced in rabbits by intravenous infusion of activated rabbit serum or C5-derived chemotactic factors. Infusion of saline, albumin, or the synthetic chemotactic peptide f-Met-Leu-Phe did not cause elevation of the serum CFI levels in rabbits. Thus, we take these data to support our hypothesis that 1) CFI is a "hyperacute phase reactant" that is elevated during inflammatory reactions, and 2) that this elevation of serum CFI activity is probably triggered by the appearance of specific C5-derived chemotactic factors within the vasculature. These studies not only provide exciting new insights into the regulatory mechanisms involved in acute inflammatory reactions but suggest that novel approaches to antiinflammatory therapy may be forthcoming.

Acute Disease↗

PubMed2000

Tumour necrosis factor-alpha and interferon-gamma synergistically activate the RANTES promoter through nuclear factor kappaB and interferon regulatory factor 1 (IRF-1) transcription factors.

Inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) synergistically activate expression of the RANTES (regulated upon activation, normal T-cell expressed and secreted) gene, which plays a crucial role in the chemoattraction of leukocytes during the inflammatory response. To understand at the molecular level the mechanism by which the two cytokines activate RANTES gene expression, we determined the requirement of cis-acting elements in the RANTES promoter and trans-acting factors. The murine RANTES promoter contained one putative interferon regulatory factor, IRF, and three putative nuclear factor kappaB (NF-kappaB) binding sites. Specific destruction of the IRF binding site and one of the three NF-kappaB binding sites abolished the inducibility of promoter activity by IFN-gamma and TNF-alpha, respectively. In contrast, mutation of the other two putative NF-kappaB binding sites did not affect RANTES promoter activity significantly. In addition, the RANTES promoter was stimulated by co-transfection of plasmids that expressed either p65, an NF-kappaB family protein, or the IRF-1 transcription factor. RANTES promoters with mutations in the NF-kappaB or IRF binding sites were not stimulated by p65 or IRF-1 expression, respectively. In electrophoretic mobility-shift and immunologic assays, we showed that IRF-1 was induced after cells were treated with IFN-gamma and that NF-kappaB was activated by TNF-alpha treatment. These results demonstrate that both NF-kappaB and IRF-1 transcription factors mediate the induction of RANTES expression via their cognate cis-acting elements when cells are stimulated by TNF-alpha and IFN-gamma.

3T3 Cells↗

PubMed2005

Metabolic syndrome is associated with markers of subclinical atherosclerosis in a French population-based sample.

Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD). The relation of MetS with early stages of atherosclerosis, more important from a prevention perspective, has not been evaluated extensively. We examined the association of MetS, using WHO and NCEP definitions, with number of carotid and femoral plaques; carotid intima-media thickness (IMT); pulse wave velocity (PWV) in a random population-based sample of 1153 French adults (35-65 year). Impact of inflammatory factors (C-reactive protein and soluble intercellular adhesion molecule-1) on these parameters was also evaluated. Prevalence of MetS was 14.5 (CI: 12.3-16.0) and 17.5 (CI: 15.1-20.2)%, using NCEP and WHO definitions, respectively. MetS significantly predicted number of plaques, IMT, and PWV after adjustment for traditional risk factors (P<0.05). Inflammatory factors predicted peripheral plaques only. The risk of subclinical atherosclerosis was considerably increased with MetS (P<0.05); odds ratios ranged 1.80-2.15 with NCEP definition, and 1.48-1.97 with WHO definition. Individuals meeting both NCEP and WHO definitions had slightly greater risk of increased plaques, IMT, and PWV. MetS was strongly associated with subclinical atherosclerosis and aortic stiffness, and can be used as a surrogate marker for high CVD risk, deserving aggressive treatment.

Adult↗

PubMed1992

Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumor necrosis factor.

Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) shift the hemostatic balance of endothelial cell surfaces in favor of prothrombotic properties by downregulating thrombomodulin (TM) and inducing tissue factor (TF) expression. We investigated the effects of retinoic acid (RA) on the prothrombotic properties of cultured umbilical vein endothelial cells exposed to TNF-alpha. The approximate 50% downregulation of TM antigen and cofactor activity induced by TNF-alpha (10 U/mL for 24 hours) was completely prevented when the cells were coincubated with both TNF-alpha and 10 mumol/L RA. In accordance with changes in cell surface TM antigen levels, the 70% decrease in TM messenger RNA (mRNA) induced by TNF-alpha was also prevented by 10 mumol/L RA. TNF-alpha induced TF activity of lysed cells (100-fold greater than untreated controls), an effect prevented when the cells were coincubated with both the TNF-alpha and 10 mumol/L RA. The 34-fold increase in TF mRNA levels induced by TNF-alpha (10 U/mL for 3 hours) was only two-fold in the presence of both TNF-alpha and RA. The effects of RA on the regulation of TM and TF expression in the cells exposed to TNF-alpha was dose-dependent from 0.01 to 10 mumol/L RA. The present results suggest that RA may affect on the mRNA level to alter TM and TF expression, effectively counteracting expression of prothrombotic properties of endothelial cells induced by inflammatory cytokines such as TNF-alpha.

Cells, Cultured↗

PubMed1996

Paradoxical effects of colchicine on the activation of human neutrophilis by chemotactic factors and inflammatory microcrystal.

Neutrophil activation by chemotactic factors and by inflammatory microcrystals is accompanied by increases in protein tyrosine phosphorylation and by the activation of the NADPH oxidase. The addition of colchicine inhibited both responses induced by triclinic monosodium urate or calcium pyrophosphate crystals. On the other hand, colchicine enhanced the tyrosine phosphorylation of specific protein in neutrophils stimulated by chemotactic factor and augmented the production of superoxide anions induced by these same agonists. The effects of colchicine were shared by other anti-microtubule agents (nocodazole and vinblastine) but not by its inactive analogue beta-lumicolchicine, trimethylcolchicinic acid, indomethacin, or phenylbutazone. Furthermore, the (enhancing as well as inhibitory) effects of colchicine on tyrosine phosphorylation and superoxide anion production were reversed by taxol. Finally, in human cytoplasts colchicine again inhibited microcrystal-stimulated tyrosine phosphorylation but did not change chemotactic factor-stimulated phosphorylation. These data strongly support the hypothesis that microtubule-related mechanisms are involved in the modulation of the tyrosine phosphorylation response in human neutrophils, and suggest that a relationship may exist between the augmentation of tyrosine phosphorylation and of the stimulation of the NADPH oxidase induced by chemotactic factors.

Adult↗

PubMed1994

[The effect of environmental factors in inflammatory bowel disease].

In an attempt to elicit risk factors in inflammatory bowel disease in Spain, we have carried out a case-control study in which we conducted personal interviews asking marital status, place of residence, economic status, use of tobacco and contraceptives, and the method of lactation in infancy. IBD was more common in patients with a low economic level; UC was predominantly found in rural population. No differences were found in the remaining categories. Our results differ from those reported from North and Central Europe.

Adult↗

PubMedDate not supplied

Production of platelet-activating factor in inflammatory exudate.

Platelet-activating factor (PAF) demonstrated a considerable increase in vascular permeability in the skin of several experimental animals, suggesting its role in inflammatory exudation. To verify the role of PAF in exudation, we also examined the effect of PAF antagonists on the exudation of rat pleurisy, and found that PAF antagonists significantly inhibited exudation induced by PAF, phorbol ester and zymosan. Furthermore we observed PAF activity in the exudate of these types of pleurisy. 50% of the PAF activity found in the exudate was of the released form and might be the cause of the increase in vascular permeability. In an in vitro study, synthesized PAF was mostly retained in the cells and less was released, suggesting that it might constitute a transient reservoir or resultant scavengers for lysophospholipids.

Animals↗

PubMed2003

Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index.

Associations between hemostatic and inflammatory markers relative to the ankle brachial index (ABI), an indicator of the presence and severity of peripheral arterial disease (PAD), are not fully understood. We studied relations among selected hemostatic factors, inflammatory markers, and the ankle brachial index (ABI) in patients with and without peripheral arterial disease (PAD). Participants were 370 men and women with ABI <0.90 and 231 patients with ABI 0.90 to 1.50 identified from noninvasive vascular laboratories and general medicine practice. Blood factors were D-dimer, prothrombin 1.2, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1), and inflammatory markers (high-sensitivity C-reactive protein [CRP], fibrinogen, and serum amyloid A [SAA]). Among patients without a history of cardiac or cerebrovascular disease, the ABI was significantly inversely associated with log D-dimer (p <0.001), log prothrombin 1.2 (p = 0.001), log CRP (p <0.001), and log fibrinogen (p = 0.005) in unadjusted analyses. In multivariable regression analyses adjusting for all blood factors as well as potential confounders, D-dimer was associated independently with ABI in participants with a history of cardiac or cerebrovascular disease (p = 0.003) and in participants without a history of cardiac or cerebrovascular disease (p = 0.017). In these analyses, CRP was associated independently with ABI among participants with a history of cardiac or cerebrovascular disease (p = 0.026). CRP was not associated independently with ABI in participants without a history of cardiac or cerebrovascular disease. We conclude that D-dimer levels may be more sensitive than other blood markers for measuring the extent of atherosclerosis in lower extremity arteries.

Aged↗

PubMed2005

Reversal of obesity-related hypoadiponectinemia by lifestyle intervention: a controlled, randomized study in obese adolescents.

CONTEXT: Hypoadiponectinemia and chronic subclinical inflammation in adults are associated with the development of diabetes and cardiovascular disease. The potential relationship between adiponectin and inflammation and its modulation by lifestyle intervention in the pediatric obese population remain unclear. OBJECTIVES: The objectives were to investigate in adolescents 1) the relationship between adiponectin and obesity-related inflammatory factors, C-reactive protein, and IL-6; and 2) the effect of a lifestyle intervention on adiponectin and whether these effects are related to changes in inflammatory factors. RESEARCH METHODS AND PROCEDURES: Twenty-one obese and age-matched lean adolescents (age, 14-18 yr; Tanner stage, > or =IV) were studied cross-sectionally. Fifteen obese adolescents also underwent a randomized, controlled physical activity-behavior-diet-based lifestyle intervention for 3 months. Associations among adiponectin, fat mass, insulin resistance, and inflammatory factors at baseline as well as after the intervention were assessed. RESULTS: Plasma adiponectin concentration was lower (P < 0.001) in the obese vs. age-matched lean adolescents. Significant inverse relationships were observed between adiponectin and inflammatory factors, insulinemia, insulin resistance, and fat mass. Intervention produced a 34% increase in adiponectin concentration (P = 0.0004) despite negligible weight loss but with reductions in fat mass, hyperinsulinemia, insulin resistance, and inflammatory factors (all P < 0.01). CONCLUSIONS: The data suggest that in adolescents, obesity-related hypoadiponectinemia is associated with subclinical inflammation, and a short-term lifestyle intervention augments adiponectin concentrations. These effects appear to be related to reductions in fat mass and inflammatory factors. Based on our current understanding of adiponectin physiology, reversal of hypoadiponectinemia in obese adolescents may protect against risks for cardiovascular disease and diabetes.

Adiponectin↗

PubMed2000

Cigarette smoking as an aggravating factor in inflammatory tissue-destructive diseases. Increase in tumor necrosis Factor-alpha priming of peripheral neutrophils measured as generation of oxygen radicals.

Stimulated neutrophils from subjects with various inflammatory tissue-destructive conditions, such as periodontal, pulmonary, gastrointestinal, and cardiovascular diseases, generate more oxygen radicals and proteases, implicated in tissue destruction, than neutrophils from healthy persons. Cigarette smoking aggravates these diseases. The aim of our study was to investigate the effect of cigarette smoking on the priming capacity of tumor necrosis factor-alpha, measured as generation of radicals from stimulated neutrophils, in smoking and non-smoking subjects with or without periodontitis. The priming effect was higher in neutrophils from smokers. In the group with periodontitis, smoking caused an even greater increase in the generation of radicals, indicating an additive effect of this local disease. The membrane expression of CD11b, CD15, and CD63 was significantly higher on neutrophils from smokers, indicating upregulated neutrophil functions. This increased priming effect of tumor necrosis factor-alpha in smokers subjects could be of importance in the aggravation of tissue-destructive inflammatory diseases.

Adult↗

PubMed1998

M-CSF: haematopoietic growth factor or inflammatory cytokine?

Macrophage colony-stimulating factor (M-CSF), initially described as a growth factor of the mononuclear phagocytic lineage, also participates in immunological and inflammatory reactions, bone metabolism and pregnancy. All its biological activities are mediated by a tyrosine kinase receptor (M-CSF-R) that is encoded by the c-fms protooncogene. After a brief overview on the synthesis, structure, metabolism and signalling of M-CSF and its receptor, we present with more details the major in vitro and/or in vivo biological activities of this cytokine. A particular attention has been devoted to the results suggesting that the various M-CSF isoforms (i.e. soluble, cell-associated and matrix anchored forms) play different specific roles on target cells bearing M-CSF-R at their surface. Infectious, inflammatory and neoplastic diseases in which M-CSF is involved and could participate to their physiopathology are mentioned. Finally, the role that the various isoforms of M-CSF could play in the regulation of "physiological and pathological cytokine networks" during inflammatory and immune responses is discussed.

Animals↗

PubMed2001

Cross-talk between pro-inflammatory transcription factors and glucocorticoids.

Asthma is a chronic inflammatory disease of the airway that is characterized by cellular infiltration and activation. These processes are induced by overexpression of chemokines and cytokines, such as eotaxin, IL-1beta and GM-CSF. These mediators are downstream targets for the transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which control the expression of most immunomodulatory genes and whose activity and expression are elevated in asthma. Glucocorticoids are the most effective anti-inflammatory drugs used in the treatment of chronic inflammatory diseases such as asthma. They act by binding to a specific glucocorticoid receptor (GR) that on activation translocates to the nucleus and either increases (transactivates) or decreases (transrepresses) the expression of responsive genes. Transrepression is the major mechanism of glucocorticoid action in inhibiting inflammatory gene expression. Thus, the ability of the transcription factors AP-1 and NF-kappaB to induce gene transcription is attenuated by GR. Although only 5-10% of asthmatic subjects are glucocorticoid-insensitive, these subjects account for over 50% of the health-care costs for asthma (> $6 billion per annum). Examining these patients also gives an insight into important aspects of glucocorticoid action in controlling inflammation and into the development of potential new drugs. Biochemical and genomic studies have indicated abnormal induction of the c-Jun N-terminal kinase (JNK) pathway in some of these patients. The ability of most patients to respond to dexamethasone with induction of histone acetylation correlated with nuclear translocation of GR. However, a subgroup of these patients had an inability to correctly interact with the basal transcription complex in spite of high levels of nuclear GR. This suggests that cross-talk between pro- and anti-inflammatory transcription factors may modulate activation of the transcriptional complex and thereby reduce steroid actions.

Acetylation↗

PubMed1997

Tumour necrosis factor and inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF) is a pleiotropic cytokine produced largely by macrophages and T lymphocytes. It has been implicated in the pathogenesis of numerous immunoinflammatory processes. Recently, a number of studies have indicated that anti-TNF antibodies may be of value in the treatment of inflammatory bowel disease. METHODS: The literature is reviewed regarding the role of TNF in the pathogenesis of inflammatory bowel disease and the results of administering TNF inhibitors. RESULTS AND CONCLUSIONS: TNF may have a role in the pathogenesis of inflammatory bowel disease. The effects of TNF inhibitors are complex and incompletely understood. Anti-TNF antibody strategies may have a role in the treatment of acute exacerbations of the disease but are unlikely to be appropriate therapies for long-term management.

Antibodies↗

PubMed2006

Effect of clopidogrel on the inflammatory progression of early atherosclerosis in rabbits model.

Atherosclerosis is an inflammatory response of the arterial wall to 'injury', which is prominently driven by inflammatory factors. Clopidogrel reduces early atherosclerosis, however, the role of clopidogrel in modulating inflammatory progression of atherosclerosis is less investigated. We wished to determine the effect of clopidogrel on progression of established atherosclerosis, vascular inflammatory factors and compared with that of aspirin and atorvastatin. Fifty male New Zealand white (NZW) rabbits were divided into five groups randomly including negative group. The rabbits were fed with a normal diet or a high cholesterol diet for 7 weeks. The right iliac artery of animals except negative group were balloon injured 1 week after initiation of the diet, then animals were treated with clopidogrel (4 mg/kg/day), aspirin (12 mg/kg/day), atorvastatin (2.5mg/kg/day) or placebo for 6 weeks. At the end of the study, the placebo (positive) group had significant progression of atherosclerosis compared with negative group. In contrast, clopidogrel, aspirin or atorvastatin treated rabbits showed a significant reduction in progression of atherosclerosis and decreased the levels of P-selection, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in serum and vascular wall. Among three drugs, the action of clopidogrel is the most powerful in decreasing the levels of inflammatory factors. These results suggest that in a rabbit atherosclerosis model, clopidogrel retards the progression of established lesions and that this effect is paralleled by a suppression of inflammatory factors.

Animals↗

PubMed2004

Critical role for granulocyte colony-stimulating factor in inflammatory arthritis.

Granulocyte colony-stimulating factor (G-CSF) is a well known regulator of granulopoiesis, but the role of endogenous G-CSF in inflammatory joint disease has not been explored. We studied the response of G-CSF-deficient mice in experimental models of joint inflammation. We show that G-CSF deficiency protects mice from acute and chronic arthritis. Reduced severity was associated with blunted mobilization of granulocytic cells from the bone marrow and less cellular infiltrate and cellular activation in inflamed joints. We also demonstrate that G-CSF blockade in established collagen-induced arthritis in WT mice markedly reduces disease manifestations and is as effective as tumor necrosis factor blockade. Our results reveal a critical role for G-CSF in driving joint inflammation and highlight G-CSF as a potential therapeutic target in inflammatory joint diseases, such as rheumatoid arthritis.

Acute Disease↗

PubMed2006

Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction.

OBJECTIVE: To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed. METHODS: Human TNF-transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed. RESULTS: Both p38 MAPK inhibitors significantly reduced clinical signs of TNF-mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin-1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK-activated protein kinase 2 (MAPKAP-2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP-2 as well as differentiation markers in cultured osteoclast precursors. CONCLUSION: These results suggest the major importance of p38 MAPK for TNF-mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.

Animals↗

PubMed2001

[The role of immune cells and inflammatory mediators in pathogenesis of intestinal inflammation].

The initiators of intestinal inflammation are greatly variable, but the mechanisms underlying the immunologically mediated mucosal damage are similar. A great progress in our understanding of the functions of gut-associated lymphoid tissue was achieved because of the advances in immuno-biology and molecular immunology. At the beginning of an inflammation microorganisms and hither to derived products or allergen firstly stimulate and activate the specific and nonspecific immune cells, and then intestine epithelials, macrophages and lymphocytes release various cytokines. These cytokines are able to recruit more immune cells to be activated and more cytokines to be released. A "cascade" is then generated between epithelials, macrophages and lymphocytes. Finally the inflammation in certain area of intestinal tract is generated. The balance between inflammatory factors and anti-inflammatory molecules depends the results of the inflammation. Therefore, the better understanding of the mechanisms on inflammatory and anti-inflammatory factors is helpful for the diagnosis and treatment of intestinal inflammation.

Animals↗