Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past, we showed differences in heterophil function between parental broilers (A [fast feathering] > B [slow feathering]) and their F1 reciprocal crosses (D [fast feathering] > C [slow feathering]). In the present study, we evaluated the linkage of the feathering gene to heterophil function, pro-inflammatory cytokine/chemokine mRNA expression levels, and resistance to Salmonella enteritidis organ invasion. Heterophils were isolated from 2-day-old chickens (C and D) separated into males and females - slow males and females (SM and SF), and fast males and females (FM and FF). Heterophil functions of degranulation and oxidative burst were measured. Heterophils from FF chickens (183+/-8.9) released more (P < 0.05) beta-d-glucuronidase (microM) than heterophils from SF chickens (149+/-3.7); FF heterophils (4.6 x 10(4)) generated a significantly (P < 0.05) greater oxidative burst (mean relative fluorescent units) compared with SF heterophils (4.2 x 10(4)). Interleukin-6, CXCLi2, and interferon-alpha mRNA expression levels were quantitated by real-time quantitative reverse transcriptase-polymerase chain reaction. No differences were observed between SM and FM or between SF and FF heterophils. Finally, 1-day-old chickens were administered S. enteritidis and liver/spleen organ invasion was quantitated. No differences were observed between the number of S. enteritidis-positive FF and SF chickens, but FM were significantly (P < 0.05) more resistant to S. enteritidis organ invasion than SM chickens. The data indicate degranulation and oxidative burst were linked with the feathering gene; however, interleukin-6, CXCLi2, and interferon-alpha mRNA expression levels were not. Furthermore, susceptibility to in vitro S. enteritidis organ invasion was not linked to the feathering gene.
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PMID:The feathering gene is linked to degranulation and oxidative burst not cytokine/chemokine mRNA expression levels or Salmonella enteritidis organ invasion in broilers. 1712 35

Inflammation facilitates tumor progression including metastasis. Interleukin-8 (IL-8) is a chemokine that regulates polymorphonuclear neutrophil (PMN) mobilization and activity and we hypothesize that this cytokine influences tumor behavior. We have demonstrated that IL-8 is crucial for PMN-mediated melanoma extravasation under flow conditions. In addition, IL-8 is up-regulated in PMNs upon co-culturing with melanoma cells. Melanoma cells induce IkappaB-alpha degradation in PMNs indicating that NF-kappaB signaling is active in PMNs. Furthermore, the production of IL-8 in PMNs is NF-kappaB dependent. We have further identified that interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) from PMN-melanoma co-cultures synergistically contribute to IkappaB-alpha degradation and IL-8 synthesis in PMNs. Taken together, these findings show that melanoma cells induce PMNs to secrete IL-8 through activation of NF-kappaB and suggest a model in which this interaction promotes a microenvironment that is favorable for metastasis.
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PMID:Regulation of interleukin-8 expression in melanoma-stimulated neutrophil inflammatory response. 1714 Dec 17

Astroglial activation constitutes a dominant response to all types of injuries of the CNS. Despite the ubiquitous nature of this cellular reaction to neural injury, a little is known concerning the signaling mechanisms that initiate it. Recently, we demonstrated that astrocytic hypertrophy and enhanced expression of glial fibrillary acidic protein resulting from toxicant-induced neurodegeneration are linked to activation of the janus kinase (JAK)-signal transducer and activator of transcription-3 (STAT3) pathway. These observations implicate ligands at the gp130 receptor as potential upstream effectors of astrogliosis. Here we used the brain slice preparation to examine potential activators of the JAK-STAT3 pathway. Following incubation of freshly cut striatal slices in phosphate-free oxygenated buffer for up to 75 min, we found that slicing the striatum itself was a sufficient stimulus to initiate a rapid activation of the JAK-STAT3 pathway as assessed with immunoblots of pSTAT3((tyr705)) using phospho-state specific antibodies. The mRNA for the gp130 cytokines, leukemia inhibitory factor, interleukin-6 and oncostatin M or the beta-chemokine, monocyte chemoattractive protein (CCl2) also were up-regulated in the slice. Moreover, we could enhance the activation of STAT3((tyr705)) by adding exogenous cytokines to the slice and we could inhibit phosphorylation of STAT3((tyr705)) by addition of tyrosine kinase inhibitors (Lav A and AG490) or neutralizing antibodies directed against leukemia inhibitory factor or oncostatin M. These data suggest that STAT3 activation is an early event in slice-induced glial activation and establishes the brain slice preparation method as a reliable model to examine the signaling mechanisms that underlie glial activation.
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PMID:Recapitulation of cell signaling events associated with astrogliosis using the brain slice preparation. 1717 61

We hypothesize an interaction between T cells/monocytes and the tubules in the development of tubulointerstitial injury in chronic proteinuric nephropathy. We established in vitro co-culture systems of proximal tubular epithelial cells (PTEC) and T cells/monocytes to study the contribution of soluble factors and cell-to-cell contact in the development of tubulointerstitial injury. The release of monocyte chemoattractant protein-1 (MCP1 or CCL2), Regulated upon Activation, normal T cell Expressed and Secreted (RANTES or CCL5), soluble intracellular adhesion molecules-1 (sICAM-1), or interleukin-6 (IL-6) was increased in PTEC following apical exposure to human serum albumin (HSA). The release of CCL2, CCL5, or sICAM-1 from PTEC was enhanced by contact of monocytes/T cells on the basolateral surface. Tumor necrosis factor-alpha (TNF-alpha) and IL-1beta are important soluble factors as suggested by the blocking effect of antibodies (Abs) against TNF-alpha or IL-1beta but not against other cytokines. The percentage of CD4+ T cells expressing both chemokine receptors, CCR2 and CCR5, was increased after culturing with supernatant from the apical or basolateral surface of PTEC following apical exposure to HSA. However, only CCR2 was upregulated in CD8+ T cells, whereas CCR5 expression was increased in monocytes. The chemotaxis of CD4+ or CD8+ T cells to supernatant from PTEC upon apical exposure to HSA was reduced with neutralizing Abs against CCL5 and/or CCL2, whereas the chemotaxis of monocytes was only reduced by anti-CCL5 but not by anti-CCL2. In summary, chemokines released by HSA-activated PTEC are amplified by monocytes/T cells. Mediators released by HSA-activated PTEC can differentially modulate the expression of chemokine receptors in monocytes/T cells and hence, alter their chemotaxis towards activated PTEC. These interactions are pivotal in the development of tubulointerstitial injury.
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PMID:Interaction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state. 1724 94

Antibody-based approaches to pneumococcal disease may hold promise for immunocompromised patients in whom vaccines are less immunogenic and/or in the context of antimicrobial resistance. Antibody-mediated protection against experimental pneumococcal pneumonia has been shown to depend on immunoregulation, but the relationship between antibody and protection against pneumococcal sepsis and immunoregulation has not been examined. Similarly, the requirement for B and T cells for antibody efficacy is not known. In this study, we determined the efficacy of the human pneumococcal capsular polysaccharide serotype 3-specific antibody, A7 (immunoglobulin M [IgM]), in secretory IgM (sIgM)(-/-), CD4(-/-), CD8(-/-), muMT(-/-), and SCID mice and investigated its effect on cytokine and chemokine expression in sera and spleens from mice with intact cellular immunity. A7 is known to be protective against systemic infection with serotype 3 and to require complement for efficacy. Compared to that of an isotype control antibody, A7 administration prolonged the survival of mice of each immunodeficient strain and was associated with a significant reduction in CFU in blood, lung, and spleen samples and a significantly reduced level of keratinocyte-derived chemokine (KC), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2) expression in normal and sIgM(-/-) mice. Studies with mice treated with penicillin revealed similar reductions in CFU and similar levels of IL-6, KC, or MIP-2 expression in A7- and penicillin-treated mice. These findings demonstrate that natural IgM and B and T cells are dispensable for A7-mediated protection against experimental pneumococcal sepsis and suggest that the efficacy of antibody-mediated protection depends on immunomodulation. Taken together, our data extend the association between antibody-mediated protection and immunomodulation to protection against systemic pneumococcal infection and to a clinically important serotype often responsible for pneumococcal sepsis.
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PMID:A human monoclonal immunoglobulin M reduces bacteremia and inflammation in a mouse model of systemic pneumococcal infection. 1730 Dec 14

We investigated the dose and time dependency of inflammatory and cytotoxic responses to size-segregated urban air particulate samples in the mouse lung. Coarse (PM10-2.5), fine (PM2.5-0.2), and ultrafine (PM0.2) particles were collected in six European cities (Duisburg, Prague, Amsterdam, Helsinki, Barcelona, Athens) in selected seasons using a modified Harvard high-volume cascade impactor. Healthy C57Bl/6J mice were intratracheally exposed to the particulate samples in a 24-h dose-response study (1, 3, and 10 mg/kg) and in 4-, 12-, and 24-h time course studies (10 mg/kg). After the exposures, the lungs were lavaged and the bronchoalveolar lavage fluid (BALF) was assayed for indicators of inflammation and tissue damage: total cell number, cell differential, total protein, and lactate dehydrogenase (LDH) and cytokine (tumor necrosis alpha [TNF-alpha], interleukin-6 [IL-6], and keratinocyte-derived chemokine [KC]) concentrations. In general, PM10-2.5 samples had higher inflammatory activity than PM2.5-0.2 samples. PM0.2 samples showed negligible inflammatory activity. PM10-2.5 and PM2.5-0.2 samples caused large increases in BALF cytokine concentrations at 4 h, but not at 12 or 24 h, after exposure. The BALF total cell number and total protein concentrations increased significantly at 12 h for both the PM10-2.5 and PM2.5-0.2 samples, but only PM10-2.5 samples produced consistent, significant increases at 24 h after exposure. There was more heterogeneity in BALF cytokine and neutrophil cell number responses to PM2.5-0.2 samples than to PM10-2.5 samples between the sampling campaigns. Thus, particle size, sources, and atmospheric transformation processes affect the inflammatory activity and response duration of urban air particulate matter in the mouse lung.
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PMID:Dose and time dependency of inflammatory responses in the mouse lung to urban air coarse, fine, and ultrafine particles from six European cities. 1736 27

Many techniques to restore cartilage defection have been tried. However, the development is still under way because of problems, including loosening of artificial joint, degenerative change of compensated tissue, risk of viral transmission via allograft/autograft, and cost of therapeutic materials for repair. In the previous research, we found that complementing cartilage defective part with carboxymethyl-chitin (CM-chitin)/beta-tricalcium phosphate composite induced regeneration of cartilage in rabbits in vivo, and it is presumable that CM-chitin plays a key role in chondrogenesis causing the regeneration of cartilage. However, the induction mechanism of chondrogenesis with CM-chitin is still unclear. In this study, we investigated the cell responses to CM-chitin by using peritoneal exudate cell (PEC) in mice and found that CM-chitin induced the expression of inflammatory cytokines and growth factors, both of which are both considered to correlate with chondrogenesis. After intraperitoneal injection CM-chitin showed enhanced expressions of mRNA of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), keratinocyte-derived chemokine, tumor necrosis factor-alpha, and transforming growth factor-beta1 (TGF-beta1) in PEC as observed by reverse transcriptase polymerase chain reaction. Productions of TGF-beta1 protein were confirmed by enzyme linked immunosorbant assay. It was also shown that mononuclear cells in PEC were responsible for the TGF-beta1 production. These results suggest that CM-chitin is an inductor of inflammatory cytokines and growth factors and may contribute to regeneration of cartilage.
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PMID:Biological roles of carboxymethyl-chitin associated for the growth factor production. 1737 66

Hypertension is a known risk factor for the development of atherosclerosis. To assess how mechanical factors contribute to this process, mouse carotid arteries were maintained in organ culture at normal (80 mm Hg) or high (150 mm Hg) intraluminal pressure for 1, 6, 12, or 24 hours. Thereafter, fluorescent human monocytic cells (U937) were injected intraluminally and allowed to adhere for 30 minutes before washout. U937 adhesion was increased in vessels kept at 150 mm Hg 12 hours (23.5+/-5.7 versus 9.9+/-2.2 cells/mm at 80 mm Hg; P<0.05) or 24 hours (26.7+/-5.7 versus 8.8+/-1.5 cells/mm; P<0.05). At 24 hours, high pressure was associated with increased mRNA expression of monocyte chemoattractant protein-1, interleukin-6, keratinocyte-derived chemokine, and vascular cell adhesion molecule-1 (6.9+/-2.1, 4.4+/-0.1, 9.8+/-2.8, and 2.4+/-0.1-fold respectively; P<0.05), as assessed by quantitative RT-PCR and corroborated by immunohistochemistry, which also revealed an increase in intracellular adhesion molecule-1 expression. Nuclear factor kappaB inhibition using SN50 peptide abolished the overexpression of chemokines and adhesion molecules and reduced U937 adhesion in vessels at 150 mm Hg. Moreover, treatment of vessels and cells with specific neutralizing antibodies established that monocyte chemoattractant protein-1, interleukin-6, and keratinocyte-derived chemokine released from vessels at 150 mm Hg primed the monocytes, increasing their adhesion to vascular cell adhesion molecule-1 but not intracellular adhesion molecule-1 via alpha4beta1 integrins. The additive effect of chemokines on the adhesion of U937 cells to vascular cell adhesion molecule-1 was confirmed by in vitro assay. Finally, pressure-dependent U937 adhesion was blunted in arteries from mice overexpressing endothelial NO synthase. Hence, high intraluminal pressure induces cytokine and adhesion molecule expression via nuclear factor kappaB, leading to monocytic cell adhesion. These results indicate that hypertension may directly contribute to the development of atherosclerosis through nuclear factor kappaB induction.
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PMID:High pressure promotes monocyte adhesion to the vascular wall. 1739 76

Heterotrimeric G(i) proteins play a role in signalling activated by lipopolysaccharide (LPS), Staphylococcus aureus (SA) and group B streptococci (GBS), leading to production of inflammatory mediators. We hypothesized that genetic deletion of G(i) proteins would alter cytokine and chemokine production induced by LPS, SA and GBS stimulation. LPS-induced, heat-killed SA-induced and heat-killed GBS-induced cytokine and chemokine production in peritoneal macrophages from wild-type (WT), Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice were investigated. LPS induced production of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-10 and interferon-gamma-inducible protein-10 (IP-10); SA induced TNF-alpha, and IL-1beta production; and GBS induced TNF-alpha, IL-6, IL-1beta, macrophage inflammatory protein-1alpha (MIP-1alpha) and keratinocyte chemoattract (KC) production were all decreased (P < 0.05) in Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice compared with WT mice. In contrast to the role of G(i) proteins as a positive regulator of mediators, LPS-induced production of MIP-1alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in macrophages from Galpha(i1/3) (-/-) mice, and SA-induced MIP-1alpha production was increased in both groups of Galpha(i) protein-depleted mice. LPS-induced production of KC and IL-1beta, SA-induced production of GM-CSF, KC and IP-10, and GBS-induced production of IL-10, GM-CSF and IP-10 were unchanged in macrophages from Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice compared with WT mice. These data suggest that G(i2) and G(i1/3) proteins are both involved and differentially regulate murine inflammatory cytokine and chemokine production in response to both LPS and Gram-positive microbial stimuli.
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PMID:Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in macrophages by Galpha(i) proteins. 1748 71

Heme is an ancient and ubiquitous molecule present in organisms of all kingdoms, composed of an atom of iron linked to four ligand groups of porphyrin. A high amount of free heme, a potential amplifier of the inflammatory response, is a characteristic feature of diseases with increased hemolysis or extensive cell damage. Here we demonstrate that heme, but not its analogs/precursors, induced tumor necrosis factor-alpha (TNF-alpha) secretion by macrophages dependently on MyD88, TLR4, and CD14. The activation of TLR4 by heme is exquisitely strict, requiring its coordinated iron and the vinyl groups of the porphyrin ring. Signaling of heme through TLR4 depended on an interaction distinct from the one established between TLR4 and lipopolysaccharide (LPS) since anti-TLR4/MD2 antibody or a lipid A antagonist inhibited LPS-induced TNF-alpha secretion but not heme activity. Conversely, protoporphyrin IX antagonized heme without affecting LPS-induced activation. Moreover, heme induced TNF-alpha and keratinocyte chemokine but was ineffective to induce interleukin-6, interleukin-12, and interferon-inducible protein-10 secretion or co-stimulatory molecule expression. These findings support the concept that the broad ligand specificity of TLR4 and the different activation profiles might in part reside in its ability to recognize different ligands in different binding sites. Finally, heme induced oxidative burst, neutrophil recruitment, and heme oxygenase-1 expression independently of TLR4. Thus, our results presented here reveal a previous unrecognized role of heme as an extracellular signaling molecule that affects the innate immune response through a receptor-mediated mechanism.
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PMID:Characterization of heme as activator of Toll-like receptor 4. 1750 83


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