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PubMedDate not supplied

Nitric oxide production in Caco-2 cells exposed to different inducers, inhibitors and natural toxins.

The involvement of the NO pathway in several intestinal inflammatory diseases is under investigation. In vitro models may provide a useful approach to better characterise this pathway at the cellular level. For this purpose, we have used Caco-2 cells, which are able to spontaneously differentiate in long-term culture to small intestine enterocytes. The effect of different NO pathway inducers [gamma-interferon (IFN-gamma) and phorbol myristate acetate (PMA)] has been studied. Our results demonstrate that Caco-2 cells constitutively express NOS at very low levels, while the induction with PMA+IFN-gamma triggers the expression of the inducible isoform with a stronger effect starting from day 14 of differentiation. The use of specific inhibitors of gene expression, at transcriptional and translational level, suggests that new synthesis of iNOS mRNA is required, through direct activation of the gene or new synthesis of transcription-required factors, as indicated by CHX inhibition. The morphological alteration induced by PMA+IFN-gamma is reversed by iNOS inhibitor, suggesting that the NO pathway may be involved in the cytoskeletal alterations. The DSP toxins, OA and DTX-1, induce NO production at levels corresponding to their different toxicity, previously detected in Caco-2 cells.

Blotting, Western↗
PubMed2005

Role of p38 MAPK in UVB-induced inflammatory responses in the skin of SKH-1 hairless mice.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway is activated by numerous inflammatory mediators and environmental stresses. We assessed the effects of ultraviolet B (UVB) on the p38 MAPK pathway and determined whether cyclooxygenase (COX)-2 expression is downstream of this kinase in the skin of UVB-irradiated SKH-1 mice. SKH-1 mice were irradiated with a single dose of UVB (360 mJ per cm2), and activation of the epidermal p38 MAPK pathway was assessed. UVB-induced phosphorylation of p38 MAPK occurred in a time-dependent manner. Phosphorylation of MAPK-activated protein kinase-2 (MAPKAPK-2) also was detected and correlated with an increase in its kinase activity. Phosphorylation of heat shock protein 27 (HSP27), a substrate for MAPKAPK-2, also was detected post-irradiation. Oral administration of the p38 inhibitor, SB242235, prior to UVB irradiation, blocked activation of the p38 MAPK cascade, and abolished MAPKAPK-2 kinase activity and phosphorylation of HSP27. Moreover, SB242235 inhibited expression of the pro-inflammatory cytokines interleukin (IL)-6 and KC (murine IL-8) and COX-2. Our data demonstrate that UVB irradiation of murine skin activates epidermal p38 MAPK signaling and induces a local pro-inflammatory response. Blockade of the p38 MAPK pathway may offer an effective approach to reducing or preventing skin damage resulting from acute solar radiation.

Animals↗
PubMed2002

A central role for the JNK pathway in mediating the antagonistic activity of pro-inflammatory cytokines against transforming growth factor-beta-driven SMAD3/4-specific gene expression.

We have focused our attention on the molecular events underlying the antagonistic activities of pro-inflammatory cytokines against transforming growth factor-beta (TGF-beta)/SMAD signaling. Using jnk1/2-knockout (jnk(-/-)) and I kappa B kinase-gamma/nemo(-/-) fibroblasts, we have determined the specific roles played by the JNK/AP-1 and NF-kappa B/Rel pathways in this phenomenon. We demonstrate that, in a cellular context devoid of JNK activity (i.e. jnk(-/-) fibroblasts), interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) did not inhibit the formation of SMAD-DNA complexes and the resulting SMAD-driven transcription in response to TGF-beta. On the other hand, lack of NF-kappa B activity in nemo(-/-) fibroblasts did not affect the antagonistic effect of pro-inflammatory cytokines against TGF-beta. In the latter cell type, overexpression of antisense c-jun mRNA or of a dominant-negative form of MKK4 blocked the inhibitory activity of TNF-alpha, similar to what was observed in normal human dermal fibroblasts. Among JNK substrates, c-Jun and JunB (but not activating transcription factor-2) antagonized TGF-beta/SMAD signaling in a JNK-dependent manner. Overexpression of JNK1 in jnk(-/-) fibroblasts restored the ability of cytokines and Jun proteins to interfere with SMAD signaling. In junAA mouse embryo fibroblasts, in which c-Jun can no longer be phosphorylated by JNK, JunB substituted for c-Jun in mediating the cytokine effect against SMAD-driven transcription in a JNK-dependent manner. These results suggest a critical role for JNK-mediated c-Jun and JunB phosphorylation in transmitting the inhibitory effect of pro-inflammatory cytokines against TGF-beta-induced SMAD signaling. In addition, we demonstrate that such a JNK-dependent regulatory mechanism underlies the antagonistic activity of TNF-alpha against TGF-beta-induced up-regulation of type I and III collagens in fibroblasts.

Animals↗
PubMed1983

C1 inactivator-C1s complexes in inflammatory joint disease.

A newly developed enzyme linked immunosorbent assay for the quantitation of C1 inhibitor (C1In)-C1s complexes was used to study activation of the classical pathway of complement in inflammatory joint diseases. Synovial fluid (SF) specimens were obtained from patients with rheumatoid arthritis (RA), other arthritides and non-inflammatory joint effusions. Paired serum (S) samples were obtained in 17 cases. Immune complexes (IC) were measured by the staphylococcal binding assay. C1In-C1s were higher in RA SF samples than in paired RAS samples (P less than 0.01). IC were higher in RA SF than non-RA SF. There was a significant inverse correlation between SF C1In-C1s complexes and SF total haemolytic complement. For all SF samples there was a correlation between IC and C1In-C1s complexes, but for RA SF alone there was no significant correlation between these parameters. There was no correlation between titre of rheumatoid factor and C1In-C1s complexes. These results demonstrate that activation of the classical pathway of complement is the hallmark of rheumatoid synovitis, yet also suggest functional heterogeneity of both circulating and intra-articular IC.

Antigen-Antibody Complex↗
PubMed2002

The inflammatory cascade in acute ischemic renal failure.

The pathogenesis of human acute ischemic renal failure is complex. Studies in animals have revealed a number of factors that could contribute to the injury associated with acute ischemic renal failure. Despite these discoveries, we have yet to devise a therapeutic regimen that will ameliorate or prevent acute renal failure in humans. Nevertheless we have made great strides in understanding mechanisms that contribute to acute ischemic renal failure. An important component is the contribution of the inflammatory cascade brought about by tissue reperfusion following an ischemic period. This review summarizes recent studies that implicate the inflammatory cells in the development of renal injury associated with acute ischemic renal failure. Because of the complex overlapping pathways involved in the inflammatory cascade, blocking single molecules is unlikely to be successful in reducing renal injury. Rather broadly abrogating the inflammatory cascade is likely to yield the greatest success in the treatment and prevention of acute ischemic renal failure.

Acute Kidney Injury↗
PubMed1990

Neutrophil activation by inflammatory microcrystals of monosodium urate monohydrate utilizes pertussis toxin-insensitive and -sensitive pathways.

The activation of leukocytes by particulates is a critical event in certain inflammatory syndromes, including acute gout associated with microcrystals of monosodium urate monohydrate. In this study we have evaluated mechanisms of human neutrophil activation by urate crystals. Both N-formyl-nor-leu-leu-phe-nor-leu-tyr-lys and uncoated urate crystals (0.5 to 5 mg/ml) but not urate crystals coated with human low density lipoprotein (which suppresses crystal-induced neutrophil responsiveness), stimulated pertussis toxin (PT)-sensitive GTPase activity in purified preparations of human neutrophil membranes. Hydroxyapatite crystals (up to 5 mg/ml) were inactive. Pretreatment of neutrophil membranes with cholera toxin also inhibited crystal-induced and formylated peptide-induced GTPase activity. Pretreatment of whole neutrophils with PT resulted in nearly complete inhibition of formylated peptide-induced cytosolic calcium mobilization, release of superoxide and release of the azurophil granule constituent alpha-mannosidase. In contrast, identical pretreatment of whole neutrophils with PT only partially suppressed urate crystal-induced alpha-mannosidase and superoxide release and failed to inhibit crystal phagocytosis and increases in cytosolic free calcium. Mechanisms of neutrophil activation by monosodium urate crystals appear to be heterogeneous in comparison with activation by formylated peptides and there is no absolute requirement for PT-sensitive membrane G proteins in neutrophil responsiveness to urate crystals.

Cell Membrane↗
PubMed1992

Immunophenotypical characterization of inflammatory cellular infiltrates in tinea.

In order to elucidate the still poorly understood pathogenetic pathways of acute tinea, the inflammatory cellular infiltrates in this infection were analyzed. Lesional punch biopsies were cryostat-sectioned and stained with monoclonal antibodies for immunophenotypization of T cells, B cells, macrophages and activation markers. For each antibody the positively stained inflammatory cells in the dermis and in the epidermis were quantified separately. Most of the dermal mononuclear cells in acute tinea were identified as T helper lymphocytes of the memory type. Furthermore, considerable amounts of Langerhans' cells and macrophages were found, but virtually no B cells. A high proportion of cells expressed markers of activation. Within the epidermis, accumulations of Langerhans' cells and LeuM5+ dendritic macrophages were detected near fungal element. In view of the otherwise rather similar cellular infiltrates in acute tinea and different non-infectious dermatoses, acute tinea may be particularly suitable to study the functional relationship of Langerhans cells and LeuM5+ macrophages.

Acute Disease↗
PubMed2004

Arginase pathway in human endothelial cells in pathophysiological conditions.

Objective. - Arginase is a nitric oxide synthase-alternative pathway for l-arginine breakdown leading to biosynthesis of urea and l-ornithine. Arginase pathway is inducible by inflammatory molecules-such as cytokines and bacterial endotoxin-in macrophages and smooth muscle cells. The presence of an arginase pathway in human endothelial cells and its possible modulation by inflammation are unknown. Methods. - We have: (i) characterised arginase pathway in terms of activity, isoform type and gene expression in a primary human umbilical vein endothelial cells (HUVEC) line; (ii) evaluated arginase functional role in cell proliferation with the aid of l-norvaline, an arginase inhibitor and (iii) determined the effects of tumour necrosis factor-alpha and endotoxin on arginase pathway. Results. - HUVEC showed a baseline arginase activity and expression of both arginase isoforms (arginase I and II (A-I and A-II, respectively)) which resulted in l-norvaline-inhibitable cellular polyamine synthesis. The baseline arginase activity is important for HUVEC proliferation as cell cycle analysis and nuclear factor Ki-67 immunostaining revealed. Following incubation with inflammatory molecules, arginase activity increased but HUVEC cell cycling decreased. Conclusions. - A-I and A-II are constitutively expressed in HUVEC where they take part to the regulation of cell cycling. Although arginase activity is positively modulated by inflammatory molecules, it is insufficient to counteract the overall cell cycling inhibiting effects of inflammation.

Antibodies, Antinuclear↗
PubMed2004

Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway.

The triggering molecular mechanism of ischemia-reperfusion injury (IRI), which in clinical settings results in excessive and detrimental inflammatory responses, remains unclear. This study analyzes the role of the TLR system in an established murine model of liver warm ischemia followed by reperfusion. By contrasting in parallel TLR knockout mice with their wild-type counterparts, we found that TLR4, but not TLR2, was specifically required in initiating the IRI cascade, as manifested by liver function (serum alanine aminotransferase levels), pathology, and local induction of proinflammatory cytokines/chemokines (TNF-alpha, IL-6, IFN-inducible protein 10). We then investigated the downstream signaling pathway of TLR4 activation. Our results show that IFN regulatory factor 3, but not MyD88, mediated IRI-induced TLR4 activation leading to liver inflammation and hepatocellular damage. This study documents the selective usage of TLR in a clinically relevant noninfectious disease model, and identifies a triggering molecular mechanism in the pathophysiology of liver IRI.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Influence of systemic treatment with cyclooxygenase inhibitors on lipopolysaccharide-induced fever and circulating levels of cytokines and cortisol in guinea-pigs.

Peripheral inflammatory stimuli result in the modification of a number of vital brain-controlled functions including the thermoregulatory set-point (induction of fever) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. We addressed the question of whether both of these components of the acute-phase response are induced by a common signal pathway. For this purpose we recorded body temperature (by remote radio-telemetry), HPA axis activity (circulating concentrations of cortisol by radio-immunoassay) and levels of the pro-inflammatory cytokines tumour necrosis factor and interleukin-6 (TNF, IL-6, using specific bioassays) in six groups of guinea-pigs. The animals received intra-arterial injections of either 10 microg/kg lipopolysaccharide (LPS) plus saline, 10 microg/kg LPS plus 5 mg/kg meloxicam (an inhibitor of the inducible form of cyclooxygenase), 10 microg/kg LPS plus 5 mg/kg diclofenac (a non-selective cyclooxygenase inhibitor), saline plus solvent, saline plus 5 mg/kg meloxicam or saline plus 5 mg/kg diclofenac. Injection of the cyclooxygenase inhibitors per se had no influence on the investigated parameters. Injection of LPS alone resulted in a biphasic fever, a more than fivefold increase in circulating cortisol and pronounced induction of TNF and IL-6. Treatment with the cyclooxygenase inhibitors either attenuated (meloxicam) or abolished (diclofenac) LPS-induced fever, but had no effect on the LPS-induced rise of plasma cortisol or IL-6. Circulating levels of TNF, in response to LPS, were enhanced by meloxicam and diclofenac, reflecting the negative feedback control exerted by prostaglandins on cytokine (specifically TNF) formation. These results provide the first evidence that the prostaglandin-dependent inflammatory pathway for fever induction is distinct from the pathway of HPA axis activation since fever, but not circulating cortisol, was attenuated by an inhibition of prostaglandin formation.

Animals↗
PubMed2003

PPAR agonists protect mesangial cells from interleukin 1beta-induced intracellular lipid accumulation by activating the ABCA1 cholesterol efflux pathway.

Previous studies have demonstrated that inflammatory cytokines such as interleukin-1beta (IL-1beta) promote lipid accumulation in human mesangial cells (HMC) by dysregulating the expression of lipoprotein receptors. Intracellular lipid accumulation is governed by both influx and efflux; therefore, the effect of IL-1beta on the efflux of lipid from HMC was investigated. IL-1beta was shown to inhibit (3)H-cholesterol efflux from HMC and increase total intracellular cholesterol concentration, probably as a result of reduced expression of the adenosine triphosphate (ATP) binding cassette A1 (ABCA1), a transporter protein involved in apolipoprotein-A1 (apo-A1)-mediated lipid efflux. To ascertain the molecular mechanisms involved, expression of peroxisome proliferator-activated receptors (PPAR) and liver X receptoralpha (LXRalpha) were examined. IL-1beta (5 ng/ml) reduced PPARalpha, PPARgamma, and LXRalpha mRNA expression. Activation of PPARgamma with the agonist prostaglandin J2 (10 micro M) and of PPARalpha with either bezafibrate (100 micro M) or Wy14643 (100 micro M) both increased LXRalpha and ABCA1 gene expression also and enhanced apoA1-mediated cholesterol efflux from lipid-loaded cells, even in the presence of IL-1beta. A natural ligand of LXRalpha, 25-hydroxycholesterol (25-OHC), had similar effects; when used together with PPAR agonists, an additive effect was observed, indicating co-operation between PPAR and LXRalpha in regulating ABCA1 gene expression. This was supported by the observation that overexpression of either PPARalpha or PPARgamma by transfection enhanced LXRalpha and ABCA1 gene induction by PPAR agonists. Taken together with previous data, it appears that, in addition to increasing lipid uptake, inflammatory cytokines promote intracellular lipid accumulation by inhibiting cholesterol efflux through the PPAR-LXRalpha-ABCA1 pathway. These results suggest potential mechanisms whereby inflammation may exacerbate lipid-mediated cellular injury in the glomerulus and in other tissues and indicate that PPAR agonists may have a protective effect.

ATP-Binding Cassette Transporters↗
PubMed2003

[What are the gastric modifications induced by acute and chronic Helicobacter pylori infection?].

H. pylori colonisation of the stomach causes the recruitment of the inflammatory cells by the adherence of the bacteria with the epithelium and the release of factors of virulence either to the contact (oipA or other soluble factors) or in the cell by translocation (CagA). Such contact triggers interleukin 8 expression in the epithelial cell and attracts lymphocytes and monocytes into the chorion. Bacterial lipopolysaccharide and urease support the activation of these inflammatory cells. The lymphocytes produce pro-inflammatory cytokines, which direct the immune response towards the Th1 pathway. The variability of the inflammatory response depends on hereditary factors of the host such as the interleukin 1 genotypes, which determine the level of the pro-inflammatory cytokine expression, and of bacterial factors such as the cag pathogenicity island, the lipopolysaccharide and the vacuolating toxin, vacA. The mucosal inflammation provokes apoptosis and atrophy of the epithelial cells through the effect of pro-inflammatory cytokines and free radicals. Epithelial proliferation is a consequence of excessive apoptosis caused by the infection. It is stimulated by the expression of inducible cyclo-oxygenase and inducible nitric oxide synthase. The development of atrophic gastritis towards cancer is supported by nitric oxide which has a mutagenic effect on DNA and inhibits p53 protein and by the bacterium itself which decreases DNA mismatch repairing activity. The gastritis induced by Helicobacter pylori changes acid secretion according to the prevalent location of the gastritis in the antrum or in the gastric body. Prevalent gastritis in the gastric body causes hypochlorhydria by reducing the release of histamin from ECL cells and inhibiting the parietal cells through the effect of tumor necrosis factor and interleukin 1-beta. Hypochlorhydria is more marked among patients having a pro-inflammatory genotype for interleukin 1-beta and those infected by bacteria with virulence factors. In the event of antrum predominant gastritis, the pro-inflammatory cytokines cause a reduction of somatostatin and gastrin releases from the D and the G cells, respectively. The result of all is increased maximal acid output and the meal-stimulated acid secretion.

Apoptosis↗
PubMed1985

The adrenochrome pathway. A potential catabolic route for adrenaline metabolism in inflammatory disease.

Polymorphonuclear leukocytes activated by latex (polystyrene) beads or the chemotactic peptide N-formyl Met Leu Phe stimulated the oxidation of adrenaline (0.3 microM-10 mM) to adrenochrome, detected spectrophotometrically at 480 nm or by a high-performance liquid chromatographic (HPLC) method. This oxidation was detectable within 5 min and continued for at least 4 hr. Over the concentration range 0.3-10 microM, more than 80% of the adrenaline oxidation occurred via the adrenochrome pathway rather than the amine oxidase-catechol methyltransferase pathway. Medium isolated after stimulation of the polymorphonuclear leukocytes retained the ability to oxidize adrenaline to adrenochrome. Serum from patients after myocardial infarction induced more oxidation of adrenaline to adrenochrome than control serum. Superoxide dismutase, catalase, and azide inhibited by 70-95% the oxidation of adrenaline to adrenochrome, either by cells or medium. Commercially available adrenochrome was biologically active, but some of the actions were due to contaminants of the preparation. HPLC of an extract of synovial fluid from a patient with rheumatoid arthritis, a fluid that contains polymorphonuclear leukocytes, showed a peak identical to that of the adrenochrome standard. The results provide a cellular mechanism for adrenochrome formation and preliminary evidence that adrenochrome can be produced in inflammatory conditions in which polymorphonuclear leukocyte infiltration occurs.

Adrenochrome↗
PubMed1999

The inhibitory effect of dexamethasone on lymphocyte adhesion molecule expression and intercellular aggregation is not mediated by lipocortin 1.

Glucocorticoids exert their anti-inflammatory activity through multiple pathways which include the inhibition of cell adhesion events. The glucocorticoid-induced protein lipocortin 1 (LC1) has reported anti-inflammatory properties and has been proposed as a putative mediator of the anti-inflammatory effects of glucocorticoids. The role of LC1 in mediating the glucocorticoid inhibition of lymphocyte adhesion and cell adhesion molecule (CAM) expression was investigated in vitro using a microaggregation assay, flow cytometry and confocal microscopy. Lymphocytes stimulated for 96 h with plastic-bound OKT3 antibody showed significant increases in LFA-1 and CD2 expression. Dexamethasone (DEX; 10(-6) M) inhibited this increase but the neutralizing anti-LC1 MoAb 1A (5 microg/ml) failed to reverse the DEX effect; neither was purified human LC1 (50 x 10(-9) M) able to inhibit CAM expression. The biological activity of the LC1 was confirmed by its ability to suppress monocyte phagocytosis and respiratory burst in response to bovine serum albumin (BSA)-anti-BSA complexes. OKT3 stimulation of cultured mononuclear cells resulted in intercellular aggregation, scored microscopically using a visual index. This aggregation was completely reversed by 10-6 M DEX but unaffected by LC1 (50 x 10(-9) M). Significant intracellular expression of lymphocyte LC1 was observed using the anti-LC1 MoAb 1B in saponin-permeabilized cells. Distribution of LC1 had a diffuse, cytoplasmic pattern. LC1 expression was reduced following 3 h treatment with 10(-6) M DEX. These findings indicate that the DEX effects on lymphocyte adhesion and CAM expression are not mediated by LC1. Thus the reported in vivo effects of LC1 on leucocyte adhesion and transmigration probably occur through functional/conformation changes of surface CAM, rather than by alteration in expression.

Annexin A1↗
PubMed2005

[Anti-inflammatory action of PPARs].

The PPARs transduce a wide variety of signals, including environmental and nutritional events, into a defined and ordered set of cellular responses at the transcriptional level. It has now been shown that all three PPAR isoforms (alpha, beta/delta and gamma) can participate in the regulation of inflammation responses. The ability of the PPARs to regulate inflammatory responses is a result of their transactivation and transrepression capacities. Most of the anti-inflammatory properties of the PPARs arise through their ability to antagonize nuclear factor-kappaB (NF-kappaB) and AP1 signaling pathways. By inhibiting these inflammatory transcription factors, the PPARs repress the expression of several genes that are involved in the inflammatory responses. In this review, I focus on emerging knowledge about PPARs roles in inflammatory responses.

Inflammation↗
PubMed2005

Immunologic mechanisms in the pathogenesis of rheumatoid arthritis.

Although much is known about the etiology and pathogenesis of rheumatoid arthritis (RA), our understanding of the immune pathways remains incomplete. The observed clinical and pathologic manifestations result from activation of several interrelated immune pathways. Current concepts of RA pathogenesis, supported by animal models, laboratory studies, and clinical observation, have reestablished and revised some of the original views. Early proposals emphasized the importance of autoantibodies and immune complexes in the initiation of RA, suggested a role for T cells in the inflammatory response characteristic of RA, and based disease perpetuation on an imbalance in the cytokine networks. We now recognize that each of these interrelated mechanisms significantly contributes to RA pathogenesis, including T cells that can help initiate and perpetuate the disease. This article reviews the major components and immune pathways involved in RA and briefly discusses the animal models that contribute to our understanding. Although a unified theory of RA pathogenesis may not be possible at this time, a paradigm is presented that considers the immune pathways that contribute to disease progression and joint destruction. These pathways may have important implications for treatment, because their modulation by biologic response modifiers (BRMs) directed toward specific targets provides benefits to patients with RA. BRMs are a new class of therapeutic agents derived from biologically active molecules and designed to modulate specific immune or inflammatory pathways. Although currently approved BRMs still have limitations, choosing an appropriate target, possibly early rather than late in the immune response, might result in new and improved therapies for RA.

Arthritis, Rheumatoid↗
PubMed1983

Activation of the alternative pathway of complement by monosodium urate monohydrate crystals and other inflammatory particles.

Activation of serum C3 by monosodium urate monohydrate (MSU) crystals and other particles was determined by immunofixation following electrophoretic separation of C3 and its activation products. Densitometry allowed quantitation of results. MSU, hydroxyapatite, brushite, and calcium pyrophosphate dihydrate crystals split C3 under conditions which demonstrate activation via the alternative pathway (AP). Quantitatively similar results were obtained in immunoglobulin deficient serum. Activation was crystal specific and was reduced by heating, grinding, sonication, and aging of crystals. Other inflammatory particles (e.g., blackthorn) activated C3 via the AP: noninflammatory particles (e.g., diamond) caused insignificant activation. It is suggested that particle-induced activation of the alternative pathway of complement may be important in the initiation of crystal-induced synovitis.

Agammaglobulinemia↗