Antiinflammatory Effects of Glucocorticoids in Brain Cells, Independent of NF-kB

Glucocorticoids are potent antiinflammatory drugs. They inhibit the expression of proinflammatory cytokines and adhesion molecules. It has recently been proposed that the underlying basis to such inhibition is the induction of the protein IkB, which inhibits the transcription factor NF-kB. The latter is a key activator of the genes encoding cytokines and adhesion molecules. The present study shows that the synthetic glucocorticoid, dexamethasone, inhibits the induction of the proinflammatory cytokine IL-8 and the adhesion molecules VCAM-1 and ICAM-1 in human 1321N1 astrocytoma and SK.N.SH neuroblastoma cells. However, dexamethasone failed to induce IkB or inhibit activation of NF-kB by IL-1 in the two cell types. EMSA confirmed the identity of the activated NF-kB by demonstrating that an oligonucleotide, containing the wild-type NF-kB-binding motif, inhibited formation of the NF-kB-DNA complexes whereas a mutated form of the NF-kB-binding motif was ineffective. In addition, supershift analysis showed that the protein subunits p50 and p65 were prevalent components in the activated NF-kB complexes. The lack of effect of dexamethasone on the capacity of IL-1 to activate NF-kB correlated with its inability to induce IkB and the ability of IL-1 to cause degradation of IkB, even in the presence of dexamethasone. The results presented in this paper strongly suggest that glucocorticoids may exert antiinflammatory effects in cells of neural origin by a mechanism(s) independent of NF-kB

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Antiinflammatory Effects of Glucocorticoids in Brain Cells, Independent of NF-kB

Glucocorticoids are potent antiinflammatory drugs. They inhibit the expression of proinflammatory cytokines and adhesion molecules. It has recently been proposed that the underlying basis to such inhibition is the induction of the protein IkB, which inhibits the transcription factor NF-kB. The latter is a key activator of the genes encoding cytokines and adhesion molecules. The present study shows that the synthetic glucocorticoid, dexamethasone, inhibits the induction of the proinflammatory cytokine IL-8 and the adhesion molecules VCAM-1 and ICAM-1 in human 1321N1 astrocytoma and SK.N.SH neuroblastoma cells. However, dexamethasone failed to induce IkB or inhibit activation of NF-kB by IL-1 in the two cell types. EMSA confirmed the identity of the activated NF-kB by demonstrating that an oligonucleotide, containing the wild-type NF-kB-binding motif, inhibited formation of the NF-kB-DNA complexes whereas a mutated form of the NF-kB-binding motif was ineffective. In addition, supershift analysis showed that the protein subunits p50 and p65 were prevalent components in the activated NF-kB complexes. The lack of effect of dexamethasone on the capacity of IL-1 to activate NF-kB correlated with its inability to induce IkB and the ability of IL-1 to cause degradation of IkB, even in the presence of dexamethasone. The results presented in this paper strongly suggest that glucocorticoids may exert antiinflammatory effects in cells of neural origin by a mechanism(s) independent of NF-kB

Antiinflammatory Effects of Glucocorticoids in Brain Cells, Independent of NF-kB

Glucocorticoids are potent antiinflammatory drugs. They inhibit the expression of proinflammatory cytokines and adhesion molecules. It has recently been proposed that the underlying basis to such inhibition is the induction of the protein IkB, which inhibits the transcription factor NF-kB. The latter is a key activator of the genes encoding cytokines and adhesion molecules. The present study shows that the synthetic glucocorticoid, dexamethasone, inhibits the induction of the proinflammatory cytokine IL-8 and the adhesion molecules VCAM-1 and ICAM-1 in human 1321N1 astrocytoma and SK.N.SH neuroblastoma cells. However, dexamethasone failed to induce IkB or inhibit activation of NF-kB by IL-1 in the two cell types. EMSA confirmed the identity of the activated NF-kB by demonstrating that an oligonucleotide, containing the wild-type NF-kB-binding motif, inhibited formation of the NF-kB-DNA complexes whereas a mutated form of the NF-kB-binding motif was ineffective. In addition, supershift analysis showed that the protein subunits p50 and p65 were prevalent components in the activated NF-kB complexes. The lack of effect of dexamethasone on the capacity of IL-1 to activate NF-kB correlated with its inability to induce IkB and the ability of IL-1 to cause degradation of IkB, even in the presence of dexamethasone. The results presented in this paper strongly suggest that glucocorticoids may exert antiinflammatory effects in cells of neural origin by a mechanism(s) independent of NF-kB

Antiinflammatory Effects of Glucocorticoids in Brain Cells, Independent of NF-kB

Glucocorticoids are potent antiinflammatory drugs. They inhibit the expression of proinflammatory cytokines and adhesion molecules. It has recently been proposed that the underlying basis to such inhibition is the induction of the protein IkB, which inhibits the transcription factor NF-kB. The latter is a key activator of the genes encoding cytokines and adhesion molecules. The present study shows that the synthetic glucocorticoid, dexamethasone, inhibits the induction of the proinflammatory cytokine IL-8 and the adhesion molecules VCAM-1 and ICAM-1 in human 1321N1 astrocytoma and SK.N.SH neuroblastoma cells. However, dexamethasone failed to induce IkB or inhibit activation of NF-kB by IL-1 in the two cell types. EMSA confirmed the identity of the activated NF-kB by demonstrating that an oligonucleotide, containing the wild-type NF-kB-binding motif, inhibited formation of the NF-kB-DNA complexes whereas a mutated form of the NF-kB-binding motif was ineffective. In addition, supershift analysis showed that the protein subunits p50 and p65 were prevalent components in the activated NF-kB complexes. The lack of effect of dexamethasone on the capacity of IL-1 to activate NF-kB correlated with its inability to induce IkB and the ability of IL-1 to cause degradation of IkB, even in the presence of dexamethasone. The results presented in this paper strongly suggest that glucocorticoids may exert antiinflammatory effects in cells of neural origin by a mechanism(s) independent of NF-kB

Loss of IκB-β Is Associated with Prolonged NF-κB Activity in Human Glial Cells

Nuclear factor-κB (NF-κB) is an inducible transcription factor central in the regulation of expression of a wide variety of genes and synthesis of several proteins involved in the generation of the immune response and inflammatory processes. In resting cells, NF-κB is maintained in an inactive state through cytoplasmic retention by IκB inhibitors. Stimulation of cells with a wide variety of inducers results in proteolytic degradation of these IκB proteins, leading to activation of NF-κB. The present study shows that interleukin-1 (IL-1) causes persistent activation of NF-κB in glial cells. Stimulation with IL-1 also causes rapid but transient degradation of IκB-α and IκB-ε. However, NF-κB remains active even after these IκB isoforms have returned to control levels. In contrast, the IκB-β isoform fails to reappear following its initial degradation by IL-1, coincident with sustained activation of NF-κB. In addition, in vivo overexpression of the various IκB isoforms revealed that IκB-β is the only isoform that has the ability to inhibit IL-1-induced NF-κB-driven transcription. The findings also suggest that the inability of IκB-α and IκB-ε to modulate NF-κB activity is due to their modification in vivo. These findings indicate that IκB-β is the key regulator of the activity of NF-κB in human glial cells