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At least 1,135 records · Page 63Linked to original sources
PubMed2006

Acute sodium overload produces renal tubulointerstitial inflammation in normal rats.

The aim of the present study was to determine whether acute sodium overload could trigger an inflammatory reaction in the tubulointerstitial (TI) compartment in normal rats. Four groups of Sprague-Dawley rats received increasing NaCl concentrations by intravenous infusion. Control (C): Na+ 0.15 M; G1: Na+ 0.5 M; G2: Na+ 1.0 M; and G3: Na+ 1.5 M. Creatinine clearance, mean arterial pressure (MAP), renal blood flow (RBF), and sodium fractional excretion were determined. Transforming growth factor beta1 (TGF-beta1), alpha-smooth muscle actin (alpha-SMA), RANTES, transcription factor nuclear factor-kappa B (NF-kappaB), and angiotensin II (ANG II) were evaluated in kidneys by immunohistochemistry. Animals with NaCl overload showed normal glomerular function without MAP and RBF modifications and exhibited a concentration-dependent natriuretic response. Plasmatic sodium increased in G2 (P < 0.01) and G3 (P < 0.001). Light microscopy did not show renal morphological damage. Immunohistochemistry revealed an increased number of ANG II-positive tubular cells in G2 and G3, and positive immunostaining for NF-kappaB only in G3 (P < 0.01). Increased staining of alpha-SMA in the interstitium (P < 0.01), TGF-beta1 in tubular cells (P < 0.01), and a significant percentage (P < 0.01) of positive immunostaining for RANTES in tubular epithelium and in glomerular and peritubular endothelium were detected in G3 > G2 > C group. These results suggest that an acute sodium overload is able 'per se' to initiate TI endothelial inflammatory reaction (glomerular and peritubular) and incipient fibrosis in normal rats, independently of hemodynamic modifications. Furthermore, these findings are consistent with the possibility that activation of NF-kappaB and local ANG II may be involved in the pathway of this inflammatory process.

Actins↗
PubMed2000

Physical and functional interaction of filamin (actin-binding protein-280) and tumor necrosis factor receptor-associated factor 2.

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an intracellular protein involved in signal transduction from TNF receptor I and II and related receptors. TRAF2 is required for TNF-induced activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and TRAF2 can also mediate activation of NF-kappaB. Here we have identified the actin-binding protein Filamin (actin-binding protein-280) as a TRAF2-interacting protein. Filamin binds to the Ring zinc finger domain of TRAF2. Overexpressed Filamin inhibits TRAF2-induced activation of JNK/SAPK and of NF-kappaB. Furthermore, ectopically expressed Filamin inhibits NF-kappaB activation induced via TNF, interleukin-1, Toll receptors, and TRAF6 but not activation induced via overexpression of NIK, a downstream effector in these pathways. Importantly, TNF fails to activate SAPK or NF-kappaB in a human melanoma cell line deficient in Filamin. Reintroduction of Filamin into these cells restores the TNF response. The data imply a role for Filamin in inflammatory signal transduction pathways.

Binding Sites↗
PubMed2006

The PI3K-NF-kappaB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis.

The anti-inflammatory effect of adenosine was previously found to be mediated via activation of the A3 adenosine receptor (A3AR). The aim of the present study was to decipher the molecular mechanism involved with the inhibitory effect of IB-MECA, an A3AR agonist, on adjuvant-induced arthritis. The adjuvant-induced arthritis rats responded to IB-MECA treatment with a decrease in the clinical score and the pathological score of the disease. The response to IB-MECA was neutralized by the antagonist MRS 1220, confirming that the efficacy of the synthetic agonist was A3AR mediated. The A3AR protein expression level was highly expressed in the synovia, in the peripheral blood mononuclear cells and in the drain lymph node (DLN) tissues of adjuvant-induced arthritis rats in comparison with naïve animals. Downregulation of A3AR expression was noted upon treatment with IB-MECA. Analysis of synovia and DLN protein extracts revealed a decreased expression level of PI3K, PKB/Akt, IKK, NF-kappaB and tumor necrosis factor alpha, known to affect survival and apoptosis of inflammatory cells, whereas the caspase-3 level was upregulated.Taken together, high A3AR expression is found in the synovia, in the immune cells in the DLN and in peripheral blood mononuclear cells. IB-MECA, an orally bioavailable molecule, activates the A3AR, inducing receptor downregulation and the initiation of a molecular mechanism that involves de-regulation of the PI3K-NF-kappaB signaling pathway. As a result, a potent anti-inflammatory effect manifested in the improvement of the disease clinical score and pathological score occurs. The finding that the A3AR expression level in the peripheral blood mononuclear cells and in the DLN reflects the receptor status in the remote inflammatory site suggests use of the A3AR as a follow-up biomarker.

Adenosine↗
PubMed1995

Biosynthesis of platelet-activating factor in normal and inflamed human colon mucosa: evidence for the involvement of the pathway of platelet-activating factor synthesis de novo in inflammatory bowel disease.

1. Platelet-activating factor can be synthesized by two distinct biochemical pathways and is degraded by a number of enzymes, the first step of which is deacetylation by a specific acetyl hydrolase. 2. The biochemical pathway of platelet-activating factor synthesis de novo and the first step in platelet-activating factor degradation have been investigated for the first time in incubates of normal human colon mucosa and in inflamed mucosa from patients with inflammatory bowel disease. 3. In the presence of 100 mumol/l CDP-choline and 100 mumol/l hexadecyl acetyl glycerol, homogenates from inflamed mucosa synthesized significantly greater platelet-activating factor [851 +/- 574 pmol/mg of protein (mean +/- SEM) in 90 min incubation] than normal mucosa [105 +/- 61 pmol/mg of protein in 90 min incubation] (P < 0.05). 4. Under the same conditions of assay, the percentage turnover to inactive lyso-platelet-activating factor was similar in inflamed mucosa (35.5 +/- 9.4%) and normal mucosa (42.7 +/- 8.5%) in 90 min (P > 0.05). 5. The identity of platelet-activating factor was confirmed by HPLC, by its mobility on TLC and by the ability of WEB 2170, a selective platelet-activating factor receptor antagonist, to block its platelet-aggregatory action. 6. These findings confirm the presence of the pathway for the synthesis de novo of the potently proinflammatory platelet-activating factor in human colon mucosa in inflammatory bowel disease.

Aged↗
PubMed2004

ICAM-1 expression is highly NF-kappaB-dependent in A549 cells. No role for ERK and p38 MAPK.

The transcription factor nuclear factor kappaB (NF-kappaB) is an activator of multiple cytokines, chemokines and adhesion molecules, which are important in inflammatory diseases such as asthma, and is consequently considered as an attractive therapeutic target. In the present study, a constitutively active dominant version of IkappaBalpha, IkappaBalphaDN, was introduced into A549 pulmonary cells by adenovirus-mediated delivery. The dominant IkappaB, but not a null viral vector, prevented the induction of NF-kappaB-dependent transcription by both tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta). Similarly, both TNFalpha and IL-1beta strongly induced mRNA and protein expression of intercellular adhesion molecule (ICAM)-1 and in each case this was prevented by adenovirus expressing the dominant IkappaB, but not by the null virus, thereby establishing ICAM-1 as an NF-kappaB-dependent gene. Numerous studies have suggested key roles for the p38 and extracellular regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascades in the activation and transactivation of NF-kappaB. We show here that SB203580, a selective inhibitor of the p38 MAPK, and PD098059 and UO126, both selective inhibitors of the ERK MAPK cascade, have no effect on TNFalpha or IL-1beta-induced translocation and DNA binding of NF-kappaB. Furthermore, these inhibitors showed no pharmacologically relevant effect on NF-kappaB-dependent transcription nor was there any effect on expression of ICAM-1. Taken together these data highlight the potential use of inhibition of the NF-kappaB signalling pathway in pulmonary inflammatory diseases and suggest that inhibitors of the p38 and ERK MAPK pathways may be of lesser effect.

Adenoviridae↗
PubMed2004

Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.

Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.

Acetylcholine↗
PubMed2006

Prevention of cochlear implant electrode damage.

PURPOSE OF REVIEW: As the current trend in cochlear implantation is to prescribe cochlear implants for patients with residual hearing and to use electroacoustic stimulation, cochlear implant damage must be prevented. This article summarizes current research endeavors to prevent electrode insertion trauma and resulting hearing loss. RECENT FINDINGS: Alteration in surgical technique is necessary with each new electrode design. Nontraumatic surgical technique also requires minimizing acoustic trauma due to drilling the cochleostomy, mechanical damage from electrode insertion, potential infection, and fibrosis of the cochlea. The pattern of hearing loss following electrode insertion trauma is an immediate loss that results from direct trauma to the macroscopic elements of the cochlea and a delayed loss that may reflect the activation of inflammatory and cell death pathways. Therapies under investigation include glucocorticoids, inhibitors of cell death pathways, and hypothermia. SUMMARY: Electrode insertion trauma-induced hearing loss involves multiple mechanisms ranging from mechanical insertion trauma to activation of inflammatory and cell death pathways. The macroscopic mechanical damage to the cochlea may be prevented by improvement of electrode design and surgical technique. The molecular damage needs further studies to assess the efficacy of novel therapeutic strategies in preserving functional residual hearing.

Animals↗
PubMed1992

Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators.

We recently proposed that endothelium may represent the primary physiologic site of synthesis of the tissue factor pathway inhibitor (TFPI). In support of this conclusion, we have now found that the poly(A)+ RNAs obtained from rabbit and bovine lung tissues contain abundant amounts of TFPI messenger RNAs (mRNAs), whereas the poly(A)+ RNAs obtained from the liver of these animals contain less than 5% of that found in the lung tissues. Because inflammatory mediators are known to upregulate tissue factor (TF) expression by the endothelium, we have examined the effect of these agents on the TFPI expression by the cultured endothelial cells. When cultured human umbilical vein endothelial cells were stimulated (in 10% fetal bovine serum) with phorbol myristate acetate (PMA), endotoxin, interleukin-1, or tumor necrosis factor-alpha, the TF mRNA increased approximately 7- to 10-fold within 2 to 4 hours. Unstimulated cells constitutively expressed TFPI mRNA and its levels either did not change or increased slightly (up to 1.5-fold) upon stimulation with these inflammatory agents. TF mRNA abruptly declined to a negligible level and the TFPI mRNA returned essentially to the basal level at approximately 24 hours. The membrane-bound TF clotting activity of induced cells peaked between 4 and 8 hours, and finally declined. The cumulative TFPI activity secreted into the media was either unchanged or slightly higher in the induced cell cultures as compared with that present in the noninduced cultures. Endothelial cells were also cultured in 10% heat-inactivated human serum derived from plasma or whole blood. TFPI secreted into the media containing whole blood serum was consistently higher (approximately 1.5-fold at 8 hours) than that secreted into the media supplemented with serum obtained from plasma lacking the formed elements; these cells also expressed similarly increased levels of TFPI mRNA. Moreover, PMA-stimulated cells cultured in whole blood serum expressed modestly increased levels of TFPI mRNA (approximately 1.5-fold); supernatants from these cells also contained similarly increased TFPI activity. Cumulatively, our data indicate that, unlike thrombomodulin and fibrinolytic enzymes synthesized by the endothelial cells, TFPI synthesis is not downregulated and may be slightly upregulated during an inflammatory response. Inspection of the 5' flanking region of the TFPI gene showed a conserved GATA-binding motif located approximately 400 bp upstream of the proposed transcription initiation site(s). This motif by binding to the GATA-2 transcriptional factor may keep the endothelium in an 'on' state for constitutive expression of TFPI.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1.

The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress and modulates pro-inflammatory cytokines. As the sepsis syndrome results from the release of pro-inflammatory mediators, we postulated that heme oxygenase-1 and its enzymatic product CO would protect against lethality in a murine model of sepsis. Mice treated with a lethal dose of lipopolysaccharide (LPS) and subsequently exposed to inhaled CO had significantly better survival and lower serum interleukin (IL)-6 and IL-1beta levels than their untreated counterparts. In vitro, mouse macrophages exposed to LPS and CO had significantly attenuated IL-6 production; this effect was concentration-dependent and occurred at a transcriptional level. The same effect was seen with increased endogenous CO production through overexpression of heme oxygenase-1. Mutation within the AP-1-binding site in the IL-6 promoter diminished the effect of CO on promoter activity, and treatment of macrophages with CO decreased AP-1 binding in an electrophoretic mobility shift assay. Electrophoretic mobility supershift assay indicated that the JunB, JunD, and c-Fos components of AP-1 were particularly affected. Upstream of AP-1, CO decreased JNK phosphorylation in murine macrophages and lung endothelial cells. Mice deficient in the JNK pathway had decreased serum levels of IL-6 and IL-1beta in response to LPS compared with control mice, and no effect of CO on these cytokine levels was seen in Jnk1 or Jnk2 genedeleted mice. In summary, these results suggest that CO provides protection in a murine model of sepsis through modulation of inflammatory cytokine production. For the first time, the effect of CO is shown to be mediated via the JNK signaling pathway and the transcription factor AP-1.

Animals↗
PubMed1993

ICAM-1-dependent pathway is not critically involved in the inflammatory process of autoimmune encephalomyelitis or in cytokine-induced inflammation of the central nervous system.

To determine whether the rat homolog of intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) we examined the effect of anti-ICAM-1 mAb, 1A29, on both active and passive EAE. We also examined its effect on a model of cytokine-induced inflammation in the central nervous system. Treatment of recipients of EAE effector cells with anti-ICAM-1 had no inhibitory activity, and in fact at high doses, treatment enhanced disease as evidenced by an earlier onset of symptoms. Treatment of active EAE with anti-ICAM-1 beginning on the day of sensitization did protect a proportion of animals from development of disease as well as reduce the severity of clinical signs in those which developed symptoms. Lymphocytes from both the draining lymph nodes and spleens of myelin basic protein (MBP)-immunized rats treated with anti-ICAM-1 failed to proliferate in response to MBP in vitro, suggesting that the antibody had prevented the animals from becoming sensitized to the antigen. Microinjection of tumor necrosis factor (TNF)-alpha into the spinal cords of rats led to the expression of ICAM-1 on vascular endothelium, and to the accumulation of leukocytes at sites of injection. The peak expression of ICAM-1 by endothelium and the peak accumulation of leukocytes following TNF alpha injection were not positively correlated. Furthermore, treatment of TNF alpha injected rats with anti-ICAM-1 did not inhibit the accumulation of leukocytes at the site of cytokine injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed2004

Molecular mechanism of diclofenac-induced apoptosis of promyelocytic leukemia: dependency on reactive oxygen species, Akt, Bid, cytochrome and caspase pathway.

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in a variety of cells, but the mechanism of this effect has not been fully elucidated. We report that diclofenac, a NSAID, induces growth inhibition and apoptosis of HL-60 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS), Akt, caspase-8, and Bid. ROS generation occurs in an early stage of diclofenac-induced apoptosis preceding cytochrome c release, caspase activation, and DNA fragmentation. N-Acetyl-L-cysteine, an antioxidant, suppresses ROS generation, Akt inactivation, caspase-8 activation, and DNA fragmentation. Cyclic AMP, an inducer of Akt phosphorylation, suppresses Akt inactivation, Bid cleavage, and DNA fragmentation. LY294002, a PI3 kinase inhibitor, enhances Akt inactivation and DNA fragmentation. Ac-IETD-CHO, a caspase-8 inhibitor, suppresses Bid cleavage and DNA fragmentation. z-VAD-fmk, a universal caspase inhibitor, but not cyclosporin A (CsA), an inhibitor of mitochondrial membrane permeability transition, suppresses DNA fragmentation. These results suggest the sequential mechanism of diclofenac-induced apoptosis of HL-60 cells: ROS generation suppresses Akt activity, thereby activating caspase-8, which stimulates Bid cleavage and induces cytochrome c release and the activation of caspase-9 and-3 in a CsA-insensitive mechanism. Furthermore, we found that 2-methoxyestradiol (2-ME), a superoxide dismutase inhibitor, significantly enhances diclofenac-induced apoptosis; that is, diclofenac combined with 2-ME may have therapeutic potential in the treatment of human leukemia.

2-Methoxyestradiol↗
PubMed2002

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-beta(1)-dependent pathway.

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-beta(1), increased the expression of PKCdelta and PKCeta, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE(2) receptor antagonists could not reverse the inhibition effect on PKCbeta(1) by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCbeta(1) attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21(waf1/cip1). Inhibition of PKCbeta(1)-mediated overexpression of p21(waf1/cip1) partially reduced the anti-apoptotic effect of PKCbeta(1). The down-regulation of PKCbeta(1) provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCbeta(1) act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.

Apoptosis↗
PubMed2002

Hyperhomocysteinaemia, coagulation pathway activation and thrombophilia in patients with inflammatory bowel disease.

BACKGROUND: The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism encoding the thermolabile variant is, when present as homozygote type (TT variant), a known genetic cause of mild hyperhomocysteinaemia (HHCY). This polymorphism has been observed in increased numbers in patients with inflammatory bowel disease (IBD). Coagulation and fibrinolysis are activated in patients with active IBD, but it is not known whether raised plasma homocysteine (HCY) found in patients with IBD significantly contributes to this activation. The aim of this study was to investigate if HHCY or presence of the TT variant significantly induces a hypercoagulable state in IBD patients receiving anti-inflammatory therapy during active disease, and to study if genetic determinants for thromboembolic disease are more frequent in these patients. METHODS: The study was designed as a cross-sectional study in an outpatient clinic comprising 106 IBD patients receiving anti-inflammatory therapy. Markers of coagulation were measured in order to elucidate whether patients with HHCY or the MTHFR TT variant were hypercoagulant compared with patients with no impairment of HCY metabolism. In addition, markers of inflammation and acute-phase reactants were measured in order to compare activity during active disease and during remission. Genetic determinants of thromboembolic disease in patients with IBD and in relevant controls were investigated in the expectation of a more frequent occurrence of these markers of thrombophilia if hypercoagulability could be a primary or contributory factor in IBD. RESULTS: No significant difference could be found in coagulation activity, acute-phase reactants or inflammatory markers in IBD patients with the TT variant of the 677C-->4T polymorphism or high (>15 micromol/L) plasma HCY levels, compared with IBD patients with no impairment of HCY metabolism. In patients with IBD, the coagulation activity was significantly increased during active disease compared with a state of remission. As expected, a significant difference regarding interleukin 6, C-reactive protein and erythrocyte sedimentation rate was present in IBD, comparing active disease with a state of remission. No significant complement activation was present in either of the groups or during active disease. Neither of the allele frequencies of genetic determinants for thrombophilia (coagulation factor V 1691G-->A (factor V Leiden) and factor II 20210G-->A polymorphisms) in the background population differed significantly from that in IBD patients. CONCLUSIONS: This study found no correlation between the MTHFR TT variant or HHCY and a hypercoagulable state in IBD patients receiving anti-inflammatory treatment. This coagulation activity is high during exacerbations of disease, but a considerable reduction is seen in patients on anti-inflammatory therapy compared with non-treated patients. Coagulation activation in IBD is probably a consequence of the inflammatory nature of the disease. That thrombophilia could be a contributory or primary factor in the development of IBD is not supported by the present study, as the frequencies for the genetic determinants for thrombophilia are similar in IBD patients and controls.

Adolescent↗
PubMed2006

The proportion of CD40+ mucosal macrophages is increased in inflammatory bowel disease whereas CD40 ligand (CD154)+ T cells are relatively decreased, suggesting differential modulation of these costimulatory molecules in human gut lamina propria.

BACKGROUND: Signal transduction through binding of CD40 on antigen-presenting cells and CD40 ligand (CD154) on T cells appears to be crucial for mutual cellular activation. Antibodies aimed at blocking the CD40-CD154 costimulatory pathway dampen the severity of experimental colitis. To elucidate the microanatomical basis for signaling through this costimulatory pathway in human inflammatory bowel disease, we studied in situ the cellular distribution of these 2 molecules on lamina propria macrophages and T cells, respectively. METHODS: Colonic specimens from 8 patients with ulcerative colitis and 8 with Crohn's disease, 8 small bowel specimens of Crohn's disease, and histologically normal control samples (6 from colon and 6 from small bowel) were included. Multicolor immunofluorescence in situ staining was performed to determine the percentage of subepithelial macrophages expressing CD40 and that of lamina propria T cells expressing CD154 while avoiding cells in lymphoid aggregates. RESULTS: The proportion of subepithelial CD40CD68 macrophages was significantly increased in normal colon compared with normal small bowel and showed further elevation in both colon and small bowel afflicted with inflammatory bowel disease. In addition, on a per-CD68-cell basis, CD40 expression was significantly increased in severely inflamed compared with moderately inflamed colonic specimens. Conversely, the proportion of CD154 T cells was similar in colon and small bowel, and interestingly, it was significantly reduced in colonic inflammatory bowel disease. CONCLUSIONS: Our findings suggested that modulation of CD40 expression by subepithelial macrophages and CD154 by lamina propria T cells is inversely modulated in the human gut.

Adolescent↗
PubMed2006

Full-length tropomyosin-related kinase B expression in the brainstem in response to persistent inflammatory pain.

Supraspinal descending pathways from the periaqueductal gray and rostral ventromedial medulla dynamically modulate nociceptive transmission in the spinal dorsal horn. We examined the expression of the brain-derived neurotrophic factor receptor trkB in response to inflammation. No difference was observed in the number of neurons expressing trkB in the periaqueductal gray or rostral ventromedial medulla 3 h after inflammation; however, by 24 h, there was a significant increase in trkB expression in the periaqueductal gray (P < 0.05) and rostral ventromedial medulla (P < 0.05), compared with naïve levels, which persisted to 7 days and returned to naïve levels by 21 days. These results demonstrate a temporal increase in the number of cells expressing trkB in response to persistent inflammation, suggesting a role for trkB signaling in activity-dependent plasticity in the pain modulatory circuitry.

Animals↗
PubMed2002

IL-17 stimulates inflammatory responses via NF-kappaB and MAP kinase pathways in human colonic myofibroblasts.

Colonic subepithelial myofibroblasts (SEMFs) may play a role in the modulation of mucosal inflammatory responses. We investigated the effects of interleukin (IL)-17 on IL-6 and chemokine [IL-8 and monocyte chemoattractant protein (MCP)-1] secretion in colonic SEMFs. Cytokine expression was determined by ELISA and Northern blotting. Nuclear factor kappa B (NF-kappaB) DNA-binding activity was evaluated by electrophortetic gel mobility shift assay (EMSA). The activation of mitogen-activated protein kinase (MAPK) was assessed by immunoblotting. IL-6, IL-8, and MCP-1 secretions were rapidly induced by IL-17. IL-17 induced NF-kappaB activation within 45 min after stimulation. A blockade of NF-kappaB activation markedly reduced these responses. MAPK inhibitors (SB-203580, PD-98059, and U-0126) significantly reduced the IL-17-induced IL-6 and chemokine secretion. The combination of either IL-17 + IL-1beta or IL-17 + tumor necrosis factor (TNF)-alpha enhanced cytokine secretion; in particular, the effects of IL-17 + TNF-alpha on IL-6 secretion were much stronger than the other responses. This was dependent on the enhancement of IL-6 mRNA stability. In conclusion, human SEMFs secreted IL-6, IL-8, and MCP-1 in response to IL-17. These responses might play an important role in the pathogenesis of gut inflammation.

Antineoplastic Agents↗