PubMed Health⌕ Search

Biomedical subjects

C Sorg

Publications and source records attributed to C Sorg.

At least 19 recordsLinked to original sources
PubMed2006

The response of the novel pro-inflammatory molecules S100A8/A9 to exercise.

Exercise shares many similarities with the acute phase response of inflammatory diseases. Recently, elevated serum levels of the novel pro-inflammatory molecules of the S100 protein family, S100A8 and S100A9, have been associated with various inflammatory diseases. The present study was conducted to assess their potential roles as inflammatory markers in monitoring the exercise-induced immune response. Seventeen male subjects of different training status performed a marathon run. Furthermore 13 subjects (10 male, 3 female) performed three different treadmill tests: strenuous (STE), moderate (MTE), and downhill (DTE). S100A8/A9 complexes were measured by ELISA, while white blood cell count (WBC) and C-reactive protein (CRP) were used as markers of the inflammatory response. Serum creatine kinase (CK) concentration was determined as a marker for muscle damage. After marathon S100A8/A9 increased dramatically during the early post-exercise period and returned to resting levels one day after the run. A similar pattern was found for WBC, while CK and CRP reached their maximum on the day after the run. Moreover, S100A8/A9 release was higher in the subgroup of well-trained athletes. The kinetic of the S100A8/A9 release after the treadmill tests depended on exercise intensity and was prolonged after eccentric exercise. In summary, the present results indicate that the novel pro-inflammatory molecules S100A8/A9 are very early and sensitive markers of the exercise-induced inflammatory response. Further investigations are necessary to evaluate the applicability of S100A8/A9 for monitoring the training process and to elucidate the dependence on training status.

Adult↗
PubMed2005

Measuring the kernel of time-dependent density functional theory with x-ray absorption spectroscopy of transition metals.

The 2p-3d core-hole interaction in the L2.3 absorption spectra of the transition metals is treated within time-dependent density functional theory. A simple three-level model explains the origin of the strong deviations from the one-particle branching ratio and yields matrix elements of the unknown exchange-correlation kernel directly from experiment.

Journal Article↗
PubMed2004

Direct observation of orbital magnetism in cubic solids.

We present x-ray magnetic circular dichroism determinations of the orbital/spin magnetic moment ratios of dilute 3d-series impurities in Au (and Cu) host matrices. This is the first direct measurement of considerable orbital moments in cubic symmetry for a localized impurity in a bulk metal host. It is shown that the unquenching of orbital magnetism depends on a delicate balance of hybridization effects between the local impurity with the host and the filling of the 3d states of the impurity. The results are accompanied by ab initio calculations that support our experimental findings.

Journal Article↗
PubMed2004

Methotrexate treatment in juvenile idiopathic arthritis: when is the right time to stop?

OBJECTIVES: To investigate whether prolonged methotrexate (MTX) treatment after induction of remission influences the subsequent duration of remission in patients with juvenile idiopathic arthritis (JIA), and to analyse the usefulness of myeloid related proteins 8 and 14 (MRP8/MRP14) as predictive markers for the stability of remission at the time when MTX is withdrawn. METHODS: Twenty five patients with oligoarticular and polyarticular JIA who received MTX to induce remission were followed up. MTX treatment was stopped after a mean of 3.8 months (group 1) or 12.6 months (group 2) after remission was documented. Differences in the number of relapses between these groups were looked for. Additionally, MRP8/MRP14 were analysed by ELISA in 22 patients. RESULTS: No difference was found in the number of relapses between patients with prolonged or early discontinued MTX treatment. Patients who were in stable remission had significantly lower MRP levels when MTX was discontinued than patients with relapses. With a cut off point for MRP8/MRP14 at 250 ng/ml, sensitivity and specificity were 100% and 70%, respectively. CONCLUSION: Longer duration of MTX treatment after induction of remission does not generally improve the status of remission in patients with JIA. Residual synovial inflammation seems to influence the rate of relapses after discontinuation of MTX treatment. MRP8/MRP14 indicate residual activity even in the absence of other laboratory or clinical signs of continuing inflammation. Normal serum concentrations of MRP8/MRP14 in clinical inactive arthritis may help to identify patients in whom MTX can be safely withdrawn after remission is achieved.

Adult↗
PubMed2003

Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis.

OBJECTIVES: Infiltration of synovial tissue by neutrophils is crucial in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and seronegative arthritis (SA). Altered vascular function and endothelial activation are important in PsA. S100A12 (EN-RAGE) is secreted by activated granulocytes and binds to the receptor for advanced glycation end products, which induces nuclear factor (NF)-kappaB-dependent activation of endothelium. METHODS: Immunohistochemical studies were performed to detect synovial S100A12 expression. We analysed serum and synovial fluid of 42 patients for S100A12 levels. RESULTS: S100A12 was strongly expressed in inflamed synovial tissue whereas it was nearly undetectable in synovia of controls or patients after successful treatment. Serum levels of S100A12 correlated with disease activity. CONCLUSIONS: Local expression of S100A12 in inflamed tissue suggests a role in synovitis, especially in PsA. High serum concentrations of S100A12 in patients with active arthritis compared with healthy controls or patients in remission point to its usefulness as a serum marker.

Adult↗
PubMed2003

Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease.

BACKGROUND: Intestinal inflammation in Crohn's disease (CD) and ulcerative colitis (UC) is characterised by an influx of neutrophils into the intestinal mucosa. S100A12 is a calcium binding protein with proinflammatory properties. It is secreted by activated neutrophils and interacts with the multiligand receptor for advanced glycation end products (RAGE). Promising anti-inflammatory effects of blocking agents for RAGE have been reported in murine models of colitis. AIMS: To investigate expression and serum concentrations of S100A12 in inflammatory bowel disease (IBD). METHODS: We performed immunohistochemical studies and immunofluorescence microscopy in biopsies from patients with CD and UC. S100A12 serum concentrations were analysed using a sandwich ELISA. RESULTS: Immunohistochemical studies revealed profound expression of S100A12 in inflamed intestinal tissue from IBD patients whereas no expression was found in tissue from healthy controls. Staining for S100A12 during chronic active CD and UC was restricted to infiltrating neutrophils. Serum S100A12 levels were significantly elevated in patients with active CD (470 (125) ng/ml; p<0.001, n=30) as well as those with active UC (400 (120) ng/ml; p<0.01, n=15) compared with healthy controls (75 (15) ng/ml; n=30). Even in inactive disease, elevated serum concentrations were found, at least in CD. S100A12 levels were well correlated with disease activity in CD and UC. CONCLUSIONS: We demonstrated that neutrophil derived S100A12 is strongly upregulated during chronic active IBD, suggesting an important role during the pathogenesis of IBD. Serum S100A12 may serve as a useful marker for disease activity in patients with IBD.

Adolescent↗
PubMed2003

Expression of S100A12 (EN-RAGE) in cystic fibrosis.

BACKGROUND: Chronic airway inflammation and recurrent infections are a core phenomenon in cystic fibrosis (CF). Diagnosing acute infectious exacerbations is difficult in the presence of chronic inflammatory processes. S100A12 exhibits proinflammatory functions via interaction with the multiligand receptor for advanced glycation end products. Blocking this interaction inhibits inflammatory processes in mice. METHODS: The expression of S100A12 in lung specimens of patients with end stage lung disease of CF was investigated, and S100A12 levels in the serum of patients with acute infectious exacerbations of CF were measured. RESULTS: Immunohistochemical studies of CF lung biopsy specimens revealed a significant expression of S100A12 by infiltrating neutrophils. High S100A12 levels were found in the sputum of patients with CF, and serum levels of S100A12 during acute infectious exacerbations were significantly increased compared with healthy controls (median 225 ng/ml v 46 ng/ml). After treatment with intravenous antibiotics the mean S100A12 level decreased significantly. There was also a significant difference between S100A12 levels in patients with acute infectious exacerbations and 18 outpatients without exacerbations (median 225 ng/ml v 105 ng/ml). CONCLUSIONS: S100A12 is extensively expressed at local sites of inflammation in CF. It is a serum marker for acute infectious exacerbations. High local expression of S100A12 suggests that this protein has a proinflammatory role during airway inflammation and may serve as a novel target for anti-inflammatory treatments.

Adolescent↗
PubMed2001

Soluble CD163 inhibits phorbol ester-induced lymphocyte proliferation.

CD163 is a member of the scavenger receptor cysteine-rich family which is expressed exclusively on human monocytes and macrophages. Upon an inflammatory stimulus the protein is shed rapidly from the membranes' surface. CD163 expression is significantly upregulated by glucocorticoids and IL-10. While the membrane-bound form of CD163 was recently identified as scavenger receptor for hemoglobin-haptoglobin complexes, there is no information about a possible role of the shed soluble CD163. It has been suggested earlier that CD163 plays a pivotal role in the downregulatory phase of inflammation. However, it has remained elusive so far as to how this protein might influence the inflammatory process. We have now identified a potential direct anti-inflammatory effect mediated by soluble CD163. The highly purified protein statistically significantly inhibits phorbol ester-induced human T-lymphocyte activation, thus attenuating the immune response to the inflammatory mediator.

Analysis of Variance↗
PubMed2001

Homocysteine inhibits tumor necrosis factor-induced activation of endothelium via modulation of nuclear factor-kappa b activity.

Homocystinuria is a metabolic disorder associated with an increased incidence of vascular disease. Here, we analyzed the effects of homocysteine on endothelial cell activation that is a prerequisite for the recruitment of leukocytes to sites of evolving atherosclerotic plaques. Exposure of human umbilical vein endothelial cells to homocysteine alone did not modulate expression of the adhesion molecules E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and the chemokines monocyte chemotactic protein-1 and interleukin-8. In contrast, tumor necrosis factor (TNF)-induced upregulation of these molecules was almost completely inhibited by homocysteine, but not by related thiol amino acids. Using electrophoretic mobility shift and reporter gene assays, the inhibitory effect of homocysteine could be attributed to inhibition of DNA binding and transcriptional activity of NF-kappa B. TNF-induced phosphorylation and degradation of I kappa B-alpha, however, were not affected. Neither was NF-kappa B-independent activation of endothelial cells by interferon-gamma influenced by homocysteine. In summary, our data indicate that homocysteine alters the response to injury of endothelial cells which may have fundamental impacts on mechanisms of leukocyte recruitment to sites of inflammation. Our findings might refer to a novel pathway by which homocysteine is involved in vascular disorders associated with homocystinuria.

Cells, Cultured↗
PubMed2001

Myeloid-related protein (MRP)-8 from cervico-vaginal secretions activates HIV replication.

OBJECTIVES: To identify a substance found in female genital tract secretions that enhances HIV expression in infected cells. DESIGN: Cervico-vaginal lavages (CVL), collected in sterile normal saline, were fractionated and tested for HIV-inducing activity using HIV-infected monocytes. METHODS: To purify the component(s) of CVL that enhance HIV production, Mono-Q ion exchange chromatography followed by Superose-12 molecular sieve analysis, and SDS--PAGE were performed. The purified protein was identified by amino acid sequence analysis. RESULTS: SDS--PAGE of bioactive fractions showed a 14 kDa polypeptide band. Amino acid sequence analysis of selected peptides from the 14 kDa band showed 100% homology with the myeloid-related protein (MRP)-8, an inflammatory protein found in mucosal secretions. Western blot analysis revealed that bioactive CVL contained more immunoreactive MRP-8 than samples without bioactivity. The HIV-inducing activity of MRP-8 was further confirmed by showing that human recombinant MRP-8 increased HIV expression by up to 40-fold. CONCLUSIONS: MRP-8 in cervico-vaginal secretions stimulates HIV production. Strategies aimed at blocking MRP-8 activity in the genital tract could reduce risk of sexual as well as maternal--infant transmission of HIV.

Amino Acid Sequence↗
PubMed2001

Interaction of S100A8/S100A9-arachidonic acid complexes with the scavenger receptor CD36 may facilitate fatty acid uptake by endothelial cells.

Recently, we showed that S100A8/A9 were secreted from phorbol ester-stimulated neutrophil-like HL-60 cells, thereby carrying arachidonic acid [Kerkhoff et al. (1999) J. Biol. Chem. 274, 32672-32679]. The present study was undertaken to evaluate whether the secreted S100A8/A9-AA complex might be involved in transcellular eicosanoid metabolism. In the presence of S100A8/A9, arachidonic acid was rapidly taken up by human umbilical vein endothelial cells in a saturable and energy-dependent fashion. Protein-facilitated arachidonate uptake was confirmed by its sensitivity toward the protein modifiers bromobimane and phloretin. Both potassium and sodium depletion did not affect the arachidonate transport, indicating that arachidonate influx was independent of endocytosis. The uptake of exogenous arachidonic acid by HUVEC was predominantly mediated by FAT/CD36. This conclusion was drawn by the findings that (i) arachidonate uptake was drastically inhibited by sulfo-N-succinimidyl oleate, a specific inhibitor of FAT/CD36; (ii) the maximal inhibition of arachidonate uptake induced by SSO was similar to that effected by ATP depletion; and (iii) the arachidonate transport was 2-fold higher in COS-7 cells transfected with the pEF.BOS-CD36 expression vector than in the empty vector-transfected COS-7 cells. Kinetic studies of arachidonate uptake were indicative for an interaction between fatty acid transporter and S100A8/A9-AA complex that was confirmed by an in vitro protein-protein interaction assay. FAT/CD36 has been suggested to be involved in inflammatory responses, and S100A8/A9 are released from activated leukocytes at inflammatory loci. Therefore, it can be envisioned that their interaction might propagate host response by perpetuating recruitment and activation of cellular effectors.

Animals↗
PubMed2001

Use of nonspecific cleavage products for protein sequence analysis as shown on calcyclin isolated from human granulocytes.

In this paper, analysis strategies developed for a sequencing problem concerning the identification of an S100 protein isolated from human granulocytes are discussed. The analysis of a trypsinized lyophilized sample suggested the presence of a number of peptides which are non-tryptic in origin. During purification of proteins from cell lysates nonspecific cleavage can be observed which may reflect biological processes and can become an unavoidable analytical problem. Current mass spectrometric software is evaluated for the analysis of nonspecific digests in this context. Matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS), high-performance liquid chromatography (HPLC)-MS/MS, and selected ion monitoring (SIM)-MS/MS have been used for peptide analysis and in addition HPLC-MS was carried out for protein analysis leading to the detection of an N-terminal modification of the protein. The success of the study is mainly due to the careful investigation of nonspecific cleavage products. Data obtained from the routine mass spectrometric analysis of an in-gel-digest allowed the identification of this protein as S100 calcium-binding protein A6-calcyclin whose expression in granulocytes has not been described so far.

Amino Acid Sequence↗
PubMed2001

Different pathways leading to cutaneous leukocytoclastic vasculitis in mice.

To investigate the pathomechanisms of leukocytoclastic vasculitis (LcV) we compared mouse models of LcV with non-vasculitic irritant contact dermatitis (ICD). Criteria for LcV as met by the immune complex-mediated Arthus reaction (Art-r) were also fulfilled by the localized Shwartzman reaction (Shw-r) and by cutaneous Loxoscelism (Lox) (injection of venom from Loxosceles reclusa containing sphingomyelinase D). After depletion of PMN (by gamma-irradiation) vessel damage could not be elicited in these models, distinguishing them from models of direct endothelial insult (necrotizing ICD). Depletion of complement could only delay, but not inhibit the Art-r, and did not change ICD, Lox or the Shw-r. The Shw-r exclusively revealed a sustained local expression of vascular adhesion molecules for 24 h in the preparatory phase (LPS s.c.), not observed in the Art-r, in Lox or ICD. Subsequent challenge with LPS i.p. was associated with upregulation of Mac-1 and ICAM-1 on PMN, but not of VLA-4 or LFA-1 (FACS analysis). Cytokines which were able to replace LPS in priming for LcV in the Shw-r (TNF-alpha and IL-1beta) also induced sustained expression of adhesion molecules, whereas IL-12 and IFN-gamma did neither. Neutralizing IL-12 or IFN-gamma also inhibited neither LcV nor sustained expression of adhesion molecules, whereas anti-TNF-alpha inhibited both. Anti-TNF-alpha had no marked inhibitory effects in the Art-r, in Lox or ICD. Combined (but not separate) neutralization of both E-selectin and VCAM-1 by antibodies suppressed LcV independent from reducing influx of PMN, proving that their sustained expression is decisive for the Shw-r and interferes with normal diapedesis. Since Loxosceles venom is known to dysregulate diapedesis and degranulation of PMN in vitro, since adherent immune complexes activate PMN at the vessel wall, and since adhesion molecules are dysregulated in the Shw-r, we suggest that LcV develops when activation of PMN coincides with vascular alterations which interfere with normal diapedesis.

Animals↗
PubMed2001

Molecular analysis of the mouse S100A9 gene and evidence that the myeloid specific transcription factor C/EBPepsilon is not required for the regulation of the S100A9/A8 gene expression in neutrophils.

The genomic locus of the mouse S100A9 (MRP14) gene, a myeloid expressed gene belonging to the S100 family, is split in three exons and two introns. Insertions of B1 like and LINE elements as well as several sequence repeat structures are scattered over the gene suggesting that this region of the S100 gene cluster has been the subject of a high mutational activity in mouse evolution. The insertions may represent molecular footprints of a recently postulated inversion event, which resulted in a rearrangement of the S100 gene cluster in mouse compared to man. Deletion analysis of the promoter reveals, that a 1200 bp fragment is able to direct a cell type-specific expression of a reporter gene in granulocytic 32D cells. Unexpectedly, the myeloid-specific transcription factor C/EBPepsilon is not needed for the transcriptional upregulation of the S100A9 and S100A8 genes in neutrophils. The data described here provide further insights into the evolution of the S100 gene cluster and into the myeloid-specific regulation of the murine S100A9 gene expression.

Animals↗
PubMed2000

In experimental leishmaniasis deficiency of CD18 results in parasite dissemination associated with altered macrophage functions and incomplete Th1 cell response.

We investigated experimental leishmaniasis in CD18-deficient mice. Whereas wild-type (WT) CD18-/- mice (129SV/C57BL/6) were resistant to infection, CD18-/- mice revealed increasing visceral dissemination of parasites. Unlike in other susceptible strains, infected footpads of CD18-/- mice did not ulcerate, due to an abolished recruitment of granulocytes. In vitro, CD18-/- macrophages were able to phagocytose opsonized Leishmania major despite absence of CR3, albeit phagocytosis rate was 50% lower than in WT macrophages. We found that uptake was partially mediated by scavenger receptors. As infected CD18-/- macrophages showed impaired ability to produce NO and to eliminate parasites, CD18 is one mediator of NO production. CD18 is also involved in reduction of IL-12 release by L. major-infected macrophages, as uptake of opsonized parasites (via CR3) decreased IL-12 release only in WT, but not in CD18-/- macrophages. When T cells from infected CD18-/- mice were restimulated with antigen-presenting cells (APC), they released no IL-2 or IL-4, but a little IFN-gamma, associated with lack of proliferation. This deficiency was linked to absence of CD18 on T cells, but not on APC. Substitution with IL-2 specifically restored a Th1-like response with proliferation and release of IFN-gamma. Thus, while impaired phagocytosis, NO production, and recruitment of granulocytes in CD18-/- mice may not reverse resistance, and while unrestricted IL-12 release supports development of Th1 cells, the failure of T cells to release IL-2 and to proliferate causes susceptibility.

Animals↗