interleukin-8 and Granuloma

Cxcl18b is a chemokine found in zebrafish and in other piscine and amphibian species. Cxcl18b is a reliable inflammatory marker; however, its function is yet to be elucidated. Here, we found that Cxcl18b is chemotactic towards neutrophils, similarly to Cxcl8a/Interleukin-8, the best characterised neutrophil chemoattractant in humans and teleosts. Like Cxcl8a, Cxcl18b-dependent recruitment required the chemokine receptor Cxcr2, while it was unaffected by depletion of the other two neutrophil receptors cxcr1 and cxcr4b. To visualise cxcl18b induction, we generated a Tg(cxcl18b:eGFP) reporter line. The transgene is induced locally upon bacterial infection with the fish pathogen Mycobacterium marinum, but strikingly is not directly expressed by infected cells. Instead, cxcl18b is induced by non-phagocytic uninfected cells that compose the stroma of the granulomas, typical inflammatory lesions formed upon mycobacterial infections. Together, these results suggest that Cxcl18b might be an important contributor to neutrophil chemotaxis in the inflammatory microenvironment and indicate that the zebrafish model could be explored to further investigate in vivo the biological relevance of different Cxcl8-like chemokine lineages.

Topics: Animals; Animals, Genetically Modified; Chemokines, CXC; Chemotaxis; Gene Knockdown Techniques; Granuloma; Inflammation Mediators; Interleukin-8; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Neutrophils; Receptors, CXCR4; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Zebrafish; Zebrafish Proteins

Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13-PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13-PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13-PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13-PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-β, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13-PE. In addition, IL-13-PE inhibited both IL-13-induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13-PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

Topics: Administration, Intranasal; Animals; Cell Proliferation; Cells, Cultured; Exotoxins; Fibroblasts; Granuloma; Inflammation; Interleukin-13; Interleukin-4 Receptor alpha Subunit; Interleukin-8; Lung; Lymphotoxin-alpha; Male; Methacholine Chloride; Mice; Pseudomonas; Receptors, Interleukin-13; Recombinant Proteins; Respiratory Hypersensitivity; Silicon Dioxide; Silicosis; Tumor Necrosis Factor-alpha; Up-Regulation

This study explores the anti-inflammatory and anti-nociceptive activities of Patrinia villosa, a Chinese medicinal plant, and to explore its effects on the proinflammatory cytokines of the rats with pelvic inflammation model. The animals were randomly divided into Patrinia villosa group (PV group), dexamethasone group (DEX group), and model-control group (CON group) to perform an ear edema test, a carrageenin-induced paw edema test, a cotton pellet-induced granuloma formation test, and an acetic acid-induced writhing test. The model rats with pelvic inflammation were established, and the serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) in each group was detected with the Enzyme-Linked ImmunoSorbent Assay (ELISA). The results of the ear edema test, carrageenin-induced paw edema test, cotton pellet-induced granuloma formation test, and acetic acid-induced writhing test all showed that Patrinia villosa had strong anti-inflammatory and anti-nociceptive effects. In the experiment using model rats with pelvic inflammation, we found that the serum levels of IL-6, IL-8 and TNF-α in PV and DEX group were all significantly lower than those of the CON group, and the serum levels of IL-6 and IL-8 in PV group were significantly lower than those of the DEX group. Patrinia villosa, with its strong anti-inflammatory and anti-nociceptive activities, can be used to treat pelvic inflammation and to relieve the associated pain.

Topics: Abdominal Pain; Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cytokines; Disease Models, Animal; Edema; Enzyme-Linked Immunosorbent Assay; Female; Gossypium; Granuloma; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Mice; Mice, Inbred ICR; Patrinia; Pelvic Inflammatory Disease; Phytotherapy; Plant Extracts; Random Allocation; Tumor Necrosis Factor-alpha

Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice.. We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni.. Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection.. Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels.. The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines.

Topics: Animals; Anthelmintics; Blood Pressure; Blood Vessels; Cytokines; Down-Regulation; Female; Granuloma; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation Mediators; Interleukin-13; Interleukin-4; Interleukin-8; Liver; Lung; Mice; Mice, Inbred C57BL; Ovum; Praziquantel; RNA, Messenger; Schistosoma mansoni; Schistosomiasis mansoni

An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor alpha (TNFalpha)-neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non-human primate model.. Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6-8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF-neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55-TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison.. Administration of TNF-neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin-12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria-induced interferon-gamma production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes.. These findings have important clinical implications for determining the mechanism of TNF neutralization-related tuberculosis.

Topics: Acute Disease; Adalimumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Chemokine CCL4; Chronic Disease; Disease Models, Animal; Granuloma; Immunosuppression Therapy; Interferon-gamma; Interleukin-12; Interleukin-2; Interleukin-8; Macaca fascicularis; Mycobacterium tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

We developed an in vitro model to study the cellular and molecular mechanisms of granulomatous inflammation in response to invading pathogens. Ichthyophonus hoferi was used as a target for encapsulation by cultivated leukocytes from the kidney of the rainbow trout (Oncorhynchus mykiss). The encapsulation process was observed over 1 week. The leukocytes were identified as either macrophages in the inner layer, or neutrophils and lymphocytes in the outer layer. The encapsulation response was inhibited by treatment with heat, but not formalin or methanol. The recognition of heat-unstable molecules on the pathogen surface could induce encapsulation. Increased expression of pro-inflammatory cytokines, such as interleukin (IL)-1beta, IL-8 and tumor necrosis factor-alpha2, was observed during encapsulation. These cytokines might play crucial roles in the encapsulation process. In particular, IL-8, which was expressed at a late phase, might recruit specific cell populations, such as the lymphocytes comprising the outer cellular layer around the target.

Topics: Animals; Cell Culture Techniques; Cell Movement; Fishes; Granuloma; Interleukin-1beta; Interleukin-8; Kidney; Leukocytes; Mesomycetozoea; Mesomycetozoea Infections; Models, Animal; Oncorhynchus mykiss; Tumor Necrosis Factor-alpha

Granuloma is a typical feature of tuberculosis. We evaluated the chemotaxis of selected human leucocyte subsets induced by macrophages incubated with Mycobacterium tuberculosis (MT)-derived products in vitro. The release of monocyte chemotactic protein 1 (MCP-1) and interleukin-8 (IL-8) correlated with the specific induction of strong chemotaxis towards monocytes and polymorphonuclear leucocytes (PMNs). gammadelta and T helper type 1 (Th1) alphabeta lymphocytes were chemoattracted, while T-resting, IL-2-activated and Th2 lymphocytes were unaffected. Activation with mycobacterium-derived, phosphate-containing components, modulated the chemokine receptor profile of gammadelta T lymphocytes as well as their pattern of cyto-chemokine production, disclosing a potential for their active participation in granuloma formation. In particular, CXCR3 and IP-10, which we found to be released by MT-pulsed alveolar macrophages, seem to represent the receptor-counter-receptor pair implicated in the chemotaxis of gammadelta lymphocytes. Immunohistochemical analysis and in situ hybridization revealed the in vivo presence of IL-8, MCP-1 and IL-10 in lymph node and lung tuberculous granulomas. Our results underscore the role of MT extracts in the induction of macrophage-derived chemokines responsible for the orchestrated recruitment of PMNs, monocytes, and Th1 and gammadelta T cells, as well as in the regulation of gammadelta function.

Topics: Antigens, Bacterial; Cells, Cultured; Chemokine CCL2; Chemokines; Chemotaxis, Leukocyte; Gene Expression; Granuloma; Humans; Interleukin-8; Lung; Lymph Nodes; Macrophages, Alveolar; Monocytes; Mycobacterium tuberculosis; Neutrophils; Receptors, Antigen, T-Cell, gamma-delta; RNA, Messenger; T-Lymphocyte Subsets

Monocyte chemoattractant protein-1 (MCP-1) but not interleukin-8 (IL-8) was detected by in situ hybridization using a nonradioactive digoxigenin-labeled complementary DNA probe in granulomatous lesions of lymph nodes from 20 pigs with naturally occurring postweaning multisystemic wasting syndrome (PMWS). Complementary DNA probes of 375 and 266 base pairs for MCP-1 and IL-8, respectively, were generated by reverse transcription-polymerase chain reaction. The 20 pigs with PMWS had distinct positive hybridization signals for MCP-1 but not for IL-8. The hybridization signals for MCP-1 were strictly confined to the cells with granulomatous lesions, including macrophages and multinucleated giant cells. A very close cell-to-cell correlation between MCP-1 and porcine circovirus 2 was seen in serial sections of lymph nodes. Results of this study indicate that MCP-1 expression may play a role in the pathogenesis of granulomatous inflammation in pigs with PMWS.

Topics: Animals; Chemokine CCL2; Circoviridae Infections; Circovirus; Granuloma; In Situ Hybridization; Interleukin-8; Lymph Nodes; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Swine; Swine Diseases; Wasting Syndrome

Angiogenesis, or new blood vessel growth, is a key process in the development of synovial inflammation in rheumatoid arthritis (RA). Integral to this pathologic proliferation are proinflammatory cytokines. We hypothesized a role for IL-18 as an angiogenic mediator in RA. We examined the effect of human IL-18 on human microvascular endothelial cell (HMVEC) migration. IL-18 induced HMVEC migration at 1 nM (p < 0.05). RA synovial fluids potently induced endothelial cell migration, but IL-18 immunodepletion resulted in a 68 +/- 5% decrease in HMVEC migration (p < 0.05). IL-18 appears to act on HMVECs via alpha(v)beta(3) integrin. To test whether IL-18 induced endothelial cell tube formation in vitro, we quantitated the degree of tube formation on Matrigel matrix. IL-18, 1 or 10 nM, resulted in a 77% or 87% increase in tube formation compared with control (p < 0.05). To determine whether IL-18 may be angiogenic in vivo, we implanted IL-18 in Matrigel plugs in mice, and IL-18 at 1 and 10 nM induced angiogenesis (p < 0.05). The angiogenesis observed appears to be independent of the contribution of local TNF-alpha, as evidenced by adding neutralizing anti-TNF-alpha Ab to the Matrigel plugs. In an alternative in vivo model, sponges embedded with IL-18 or control were implanted into mice. IL-18 (10 nM) induced a 4-fold increase in angiogenesis vs the control (p < 0.05). These findings support a novel function for IL-18 as an angiogenic factor in RA and may elucidate a potential therapeutic target for angiogenesis-directed diseases.

Topics: Angiogenesis Inducing Agents; Animals; Arthritis, Rheumatoid; Cell Division; Cell Line; Cell Migration Inhibition; Cell Movement; Chemokine CXCL5; Chemokines; Chemokines, CXC; Chemotactic Factors; Collagen; Drug Combinations; Drug Implants; Endothelium, Vascular; Granuloma; Humans; Immune Sera; Interleukin-18; Interleukin-8; Laminin; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Porifera; Proteoglycans; Receptors, Vitronectin; Recombinant Proteins; Synovial Fluid; Tumor Necrosis Factor-alpha

In berylliosis and other granulomatous diseases the macrophage is regarded as effector cell in granuloma formation. However, little is known about granuloma-associated regulation of genes in these cells. Differential display reverse transcription polymerase chain reaction (DDRT-PCR) is an attractive method for detection of differentially expressed genes. Since DDRT-PCR requires a comparably low quantity of RNA, its application to rare and limited amounts of clinical samples is convenient. In the present study we applied DDRT-PCR in a multiple and complex comparison of expressed sequence tags induced in response to various granuloma-associated and control stimuli. Since we are interested in granuloma-restricted changes, we tested peripheral blood monocytes from berylliosis patients by DDRT-PCR stimulated with up to nine different stimuli, including BeSO4, the causal agent of berylliosis. Comparison of a total of 1663 sequence tags in four berylliosis patients revealed a mean of 32.5-37.4% differentially regulated sequence tags in peripheral blood monocytes of berylliosis patients, caused by stimuli including beryllium or Mycobacterium tuberculosis and control stimuli such as Latex or Zymosan. In 7.7-28.0% of the analyzed sequence tags we detected a differential regulation restricted to the presence of granuloma-associated stimuli BeSO4, HgS, LiCO3, NiSO4, lipopolysaccharide, and/or heat killed M. tuberculosis; 1.4-12.3% were induced by more than one granuloma-associated stimulus. Alterations associated with BeSO4 and one of the named stimuli were detected in 1.4-4.5%. An exclusive association with BeSO4 was found in 2.6-5.7% of the analyzed sequence tags.

Topics: Adult; Berylliosis; Beryllium; Cells, Cultured; Female; Gene Expression Regulation; Granuloma; Humans; Interferon-gamma; Interleukin-2; Interleukin-6; Interleukin-8; Male; Middle Aged; Monocytes; Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Bacterial Infections; Chemotactic Factors; Chronic Disease; Granuloma; Humans; Immunity, Cellular; Interleukin-8; Malaria; T-Lymphocytes; Tuberculosis

A 69-year-old woman had plasma cell granuloma of the left middle lobe of the lung. Her symptoms and roentgenologic findings improved with antibiotic treatment. Before treatment, the number of neutrophils and NCA were markedly increased in BAL fluid obtained from the affected region of the left lung and moderately increased in BAL fluid obtained from the nonaffected region of the right lung. The number of neutrophils, the NCA as well as the contents of C5 and C5a des Arg (neutrophil chemotactic factors) in the BAL fluids from both these regions decreased during treatment. These findings suggest that plasma cell granuloma was due to chronic immune and inflammatory reactions in the lung, that neutrophils are involved in development of the symptoms and signs of this disease, and that neutrophil chemotactic factors, including complement-derived factors, are important in neutrophil recruitment at the lesion and in nonaffected parts of the lung.

Topics: Aged; Albumins; Bronchoalveolar Lavage Fluid; Cell Count; Chemotactic Factors; Complement C5; Female; Granuloma; Granuloma, Plasma Cell; Humans; Immunoglobulins; Interleukin-8; Lung Diseases; Neutrophils; Radiography