Defective NF-κB Signaling in Dedifferentiated Hepatoma Cells

Dedifferentiated rat hepatoma cells contain defects that result in the loss of hepatic gene expression, including the liver-enriched HNF4/HNF1 pathway. We examined induction of NF-B, a key mediator of the inflammatory response, in hepatoma and dedifferentiated hepatoma cells. We show that exposure of dedifferentiated hepatoma cells, but not rat and human hepatoma cell lines, to proinflammatory cytokines or lipopolysaccharide resulted in rapid and sustained NF-B induction. IB- levels, but not NF-B subunit p65 or IB- levels, were elevated compared with those for parental hepatoma cells. Interestingly, LPS-mediated activation of NF-B was found to be independent of degradation of IB- or IB-. Thus, these results suggest that loci responsible for maintaining hepatic gene expression also influence cellular responses to inflammatory agents.     

A decision between life and death during TNF-alpha-induced signaling

Tumor necrosis factor- (TNF-), a proinflammatory cytokine, exerts its biological activity by signaling via its two receptors, TNF-RI and TNF-RII, and by activating NF-B. NF-B is essential for survival of many cell types; however, TNF- also induces cell death. In this article, both the survival and cell death signaling by TNF- and the role of caspases in turning off NF-B survival signal are reviewed. Furthermore, a role of DAP kinase in TNF-induced apoptosis is discussed. Finally, the molecular basis of the effect of age on TNF--induced apoptosis in human T cells is reviewed.     

Rifampicin Inhibits CD95-Mediated Apoptosis of Jurkat T Cells via Glucocorticoid Receptors by Modifying the Expression of Molecules Regulating Apoptosis

Rifampicin and its analogues are increasingly used in the treatment and prophylaxis of mycobacterial infections. Recently, it has been demonstrated that rifampicin binds to and activates glucocorticoid receptors (GR). Glucocorticoids may inhibit or promote apoptosis in various cell types. Therefore, we investigated the effect of rifampicin on anti-CD95-induced apoptosis in Jurkat T cells. Rifampicin, in a concentration-dependent manner, inhibited anti-CD95-induced apoptosis. Furthermore, rifampicin down-regulated the expression of Bax and CD95L and up-regulated the expression of Bcl-2, Bcl-x_L, and Flice-inhibitory protein-L (FLIP_L); however, rifampicin had no effect on CD95 or XIAP expression. Rifampicin did not inhibit the binding of anti-CD95 monoclonal antibody to CD95 receptor. A GR-specific antagonist RU480 reversed the inhibition of apoptosis by rifampicin. Furthermore, rifampicin failed to inhibit anti-CD95-induced apoptosis in a dominant negative IB (IBM) Jurkat T cells. Taken together, these findings suggest that rifampicin inhibits anti-CD95-induced apoptosis in Jurkat T cells by modulating the expression of various molecules regulating apoptosis and its effect appears to be mediated via GR and at least in part through NF-B signaling pathway.     

Synoviocytes in chronic synovitis in situ and cytokine stimulated synovial cells in vitro neo-express α1, α3 and α5 chains of β1 integrins

The expression of the 1 integrins was examined immunohistochemically in synoviocytes from normal synovial membrane and from chronic synovitis of different aetiology and intensity. Normal synoviocytes were 61-positive but lacked 1 through 5. In mild inflammation type A synoviocytes neo-expressed 1, 3, and 5 chains. In severe inflammation both type A and B synoviocytes expressed 3, 4, 5, and 6 chains. The effects of inflammatory cytokines, as single agents or in combination, on the 1 integrin expression in cultured normal synoviocytes was determined by immunocytochemistry and flow cytometry. The 1 chain, while absent in unstimulated synoviocytes, was induced by interleukin-1 (IL-1), tumour necrosis factor- (TNF-), and interferon- (INF-). This effect was enhanced by combining IL-1 and TNF-. Expression of the 3 chain was up-regulated by IL-1 and, more intensely, by IFN-. Transforming growth factor (TGF-) inhibited the up-regulating effect of IL-1 and antagonized the effect of IFN- on 3 chain expression. Expression of the 5 chain was up-regulated significantly by co-stimulation through IL-1 together with TGF- or TNF-. Thus, the 1 integrin profile of cytokine activated synoviocytes in vitro resembled that of synoviocytes in synovitis in situ. These data suggest that IL-1, TNF-, IFN-, and TGF- are likely to be among the effectors regulating 1 integrin expression in synoviocytes in vivo.     

Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic,diabetic-prone BB rats: Attenuation by drug intervention decreases inflammatory cell infiltration and incidence of diabetes

Objective and Design: To document in vivo immunolocalization and activation of nuclear factor-B (NF-B) and inducible nitric oxide synthase (iNOS) expression in prediabetic stages of diabetes mellitus.Material or Subjects: Genetic, diabetic-prone or diabetic-resistant BB rats (total = 189).Treatment: Various doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine (2.5 mg/kg) starting at 30 or 60 days of age.Methods: Immunohistochemistry, electrophoretic mobility shift assays, plasma glucose.Results: NF-B and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-B and iNOS was largely confined to islets and occurred in diabetic-prone rats prior to overt hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease and decreased the incidence of hyperglycemia to levels achieved by immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive NF-B and iNOS within pancreatic islets.Conclusions: These studies support a role of NF-kB and iNOS in diabetogenesis in vivo.Received 7 Februar 2003; returned for revision 24 April 2003; accepted by J.S. Skotnicki 1 September 2003     

Ultrastructural evidence for colocalization of κ light chain-and β2-microglobulin-derived amyloids using double labelling immunogold electron microscopy

In systemic amyloidosis, it is essential to decide what type of amyloid protein is deposited in tissues before the therapy can be selected and the prognosis assessed in each patient. We examined tissues affected by amyloid deposition from a patient with multiple myeloma by immunohistochemistry and double labelling immunogold electron microscopy and demonstrated colocalization of light chain- and ₂-microglobulin-derived amyloids in the same tissue. ₂-Microglobulin-derived amyloid had ultrastructurally characteristic features that distinguished it from light chain-derived amyloid. This is the first report of the colocalization of two different amyloids by immunoelectron microscopy.     

Reconstitution of chemokine-induced actin polymerization in undifferentiated human leukemia cells (HL-60) by heterologous expression of interleukin-8 receptors

The chemokines interleukin-8 (IL-8) and GRO bind in neutrophils to the interleukin-8 receptor and (IL-8R and ) triggering reorganization of the actin cytoskeleton and activation of phospholipase C (PLC). Reconstitution of chemokine-induced activation of PLC indicated coupling of IL-8R and to pertussis toxin-insensitive or . To identify the signal transduction mechanisms of chemokine-induced actin response, undifferentiated human leukemia cells (HL-60 cells) constitutively expressing , and were chosen for reconstitution studies. Expression of recombinant receptors after transfection of the cells with the cDNA of IL-8R and was confirmed by binding studies with radiolabeled ligands. IL-8R bound IL-8 with high affinity (Kd1 nM) and GRO with low affinity (Kd 1 M), whereas IL-8R bound both IL-8 and GRO with high affinity (Kd1 nM). Flow cytometric actin measurements indicated that high affinity ligand-receptor interactions in both receptor transfectants displayed inducible responses. Pretreatment of transfectants with pertussis toxin caused ADP-ribosylation of G-proteins and blocked chemokine-induced polymerization, indicating involvement of or , but not in this response.accepted by M.J. Parnham     

Flow Cytometric Analysis of In Vitro Proinflammatory Cytokine Secretion in Peripheral Blood from Multiple Sclerosis Patients

The cytokines, interferon- (IFN-), tumor necrosis factor- (TNF-rpar;, and interleukin-2 (IL-2) are important endogenous proinflammatory proteins and have been linked to disease activity in multiple sclerosis. In this study, we use flow cytometric methodology to compare the secretion of IFN-, IL-2, and TNF- from peripheral blood-derived T cells of multiple sclerosis patients to the secretion in healthy controls. The percentages of IFN-, IL-2, and TNF- secreting cells are not significantly different between multiple sclerosis patients and controls. However, the TNF- secreting CDS cell percentage is correlated with the IFN- and IL-2 secreting CD3 cell percentages in multiple sclerosis patients. In the controls, only the TNF- secreting CD3 cell percentage is correlated with IFN-. These findings show that correlated secretion of cytokines occurs in multiple sclerosis and suggest that concerted intercytokine interactions may play an important role in the disease.     

Synergistic effects of tumour necrosis factor-α and interferon-γ on feline haemopoietic progenitors

Pathogenic mechanisms that underlie feline leukaemia virus subgroup-C (FeLV-C) induced erythroid aplasia are unknown. FeLV-C infection is associated with higher serum levels of interferon- (IFN-) and tumour necrosis factor- (TNF-), which may act synergistically to cause haemopoietic suppression. In the present studies, the synergistic effects of TNF- and IFN- on feline bone marrow progenitors in vitro were evaluated. Bone marrow mononuclear cells from specific-pathogen-free cats were exposed to TNF- (100 and 200 pg/ml) and IFN- (100 or 200 units/ml), alone or in combination, for 2 h before plating for clonal assays of colony forming units. Our results show that TNF- and IFN- in combination caused marked suppression of feline colony forming units-erythroid (CFU-E), burst forming units-erythroid (BFU-E), and colony forming units-fibroblasts (CFU-F), whereas colony forming units-granulocyte/macrophage (CFU-GM) were minimally affected. The same concentrations of TNF- and IFN- alone had minimal effects on CFU-E, BFU-E and CFU-F. These results suggest that TNF- and IFN- may play a significant role in regulating haemopoiesis in cats and may be involved in the pathogenesis of erythroid aplasia in cats infected with feline leukaemia virus.     

Increase in TCRγδ T lymphocytes in synovia from rheumatoid arthritis patients with active synovitis

To determine the relative presence of TCR+ and TCR+ T cells in synovial tissue from patients with various types of inflammatory synovitis and in tissues from patients with a number of chronic T cell-mediated conditions, we stained frozen tissue sections with monoclonal antibodies in indirect immunofluorescence assays. In tissues obtained from patients with chronic T cell-mediated granulomatous conditions (Wegener's granulomatosis, lymphomatoid granulomatosis, granuloma annulare, Langerhan's cells granulomatosis, pigmented villonodular synovitis, Takayasu's arteritis, and talc granulomatosis), the T cells present were predominantly TCR+, without an increased presence of TCR+ cells. In contrast, 6 of 14 (43%) synovia from patients with rheumatoid arthritis (RA) showed increased TCR+ T cells (3–10 cells/hpf). The RA synovia with increased TCR+ cells present had an increased tissue inflammation score compared to RA synovia with few TCR+ cells [18.6±5.8 versus 11.6±4.2 (mean±SE),P<0.05]. In contrast, synovia from patients with osteoarthritis, systemic lupus erythematosus, and trauma did not show an increased presence of TCR+ T cells. Thus, in cellular inflammatory infiltrates the presence of increased TCR cells is not a component of noninfectious granulomatous inflammation but is found in approximately 40% of RA synovia with high levels of inflammation.     

The role ofγδ T cells in the normal and disordered immune system

Summary A small population of T cells does not express the conventional T cell receptor characterized by the and polypeptide chains (TCR) but instead, two polypeptides termed and (TCR). This alternative receptor is able to recognize antigen. It appears early in T cell ontogeny, but its role in the thymus prior to the availability of TCR remains unclear. In selected sites such as skin or gut TCR predominates in mice which might suggest a role of T cells in the first line of defense against infection, T cells secrete lymphokines and display cytotoxic activity. However, their activation requirements may differ from what is known for T cells since MHC-nonrestricted and also CD4 and CD8 negative T cells have been described. Preferential activation by mycobacterial antigens possibly indicates a special repertoire of the T cells. In various diseases slightly increased numbers of T cells were found, but these preliminary studies have not yet provided evidence for a major pathogenetic role of T cells.List of abbreviations C constant region (immunoglobulin or TCR gene segment) - CD4 cluster of differentiation 4 (mainly on helper cells) - CD8 cluster of differentiation 8 (mainly on cytotoxic cells) - D diversity region (immunoglobulin or TCR gene segment) - DNA desoxyribonucleic acid - IL2 interleukin 2 - J joining region (immunoglobulin or TCR gene segment) - kD kiloDalton - MHC major histocompatibility complex - NK natural killer (cells) - RA rheumatoid arthritis - TCR T cell receptor - V variable region (immunoglobulin or TCR gene segment)     

Acute Alcohol Consumption Attenuates Interleukin-8 (IL-8) and Monocyte Chemoattractant Peptide-1 (MCP-1) Induction in Response to Ex Vivo Stimulation

Chronic alcohol use is associated with impaired immunity and host defense. Even acute ethanol treatment both in vitro and in vivo has been shown to result in decreased inflammatory cytokine production. However, the potential immunoregulatory effects of acute, moderate alcohol use are yet to be fully explored. Here we show that in vitro acute alcohol treatment of normal blood monocytes resulted in a significant, dose-dependent (25–100 mM) attenuation of staphylococcus enterotoxin B (SEB), phytohemagglutinin (PHA), or IFN-induced monocyte IL-8 and MCP-1 production (P < 0.01). Likewise, ethanol (100 mM) in vitro reduced MCP-1 levels in response to SEB, PHA, or IFN stimulation in mononuclear cells (31–62% reduction). Furthermore, acute alcohol consumption (0.85 g/kg body weight) significantly attenuated SEB- or LPS-induced IL-8 and MCP-1 levels in whole-blood samples obtained 4 hr after alcohol consumption from normal nonalcoholic individuals (P < 0.01). RANTES and MIP-1 were only minimally inhibited (16–25% inhibition) by in vitro ethanol (100 mM) in mononuclear cells, suggesting that ethanol may have a selective effect on the regulation of various chemokines. These results demonstrate that acute alcohol, in vivo as well as in vitro, attenuates monocyte-derived chemokine production in response to a subsequent immune challenge. Our data show for the first time that activation of nuclear regulatory factor B (NF-B), a common regulator binding in the promoter region of IL-8 and MCP-1 genes, is inhibited by acute ethanol (25 mM) treatment in SEB-stimulated human monocytes. These results imply that inhibition of NF-B activation may be one of the intracellular mechanisms for the ethanol-induced inhibition of IL-8 and MCP-1 production in monocytes. Thus, impaired chemokine (particularly MCP-1 and IL-8) induction upon an immune challenge is likely to contribute to compromised host defense after acute alcohol consumption and may also affect progression of diseases such as atherosclerosis or HIV infection where chemokines contribute to progression of the disease.     

GM-CSF counteracts hemorrhage-induced suppression of cytokine-producing capacity

Objective and design: To study whether a treatment with the hematopoietic growth factor GM-CSF restores the attenuated ex-vivo cytokine-producing capacity of macrophages after sublethal hemorrhagic shock.Subjects: Male Sprague-Dawley rats.Treatment: 20 g/animal of recombinant murine GM-CSF after shock via arterial line.Methods: Hemorrhagic shock was established by pressure-controlled bleeding to a mean arterial pressure of 50 mm Hg for 35–40 min and consecutive resuscitation. 24 h after hemorrhage, lipopolysaccharide (LPS)-induced cytokine production of isolated macrophages derived from different compartments was measured.Results: A significant reduction of LPS-induced TNF production was found in whole blood cultures (1.0 ± 0.7 ng/ml after sham vs. 0.23 ± 0.08 ng/ml after shock operation), macrophages derived from spleen (0.88 ± 0.23 ng/ml after sham vs. 0.03 ± 0.1 ng/ml after shock operation), peritoneum (2.2 ± 0.7 ng/ml after sham vs. 0.29 ± 0.4 ng/ml after shock operation) and bronchoalveolar fluid (0.65 ± 0.13 ng/ml after sham vs. 0.003 ± 0.027 ng/ml after shock operation, mean ± S.D.). In cells from animals treated with GM-CSF a significantly enhanced LPS-induced TNF production in splenic, alveolar and peritoneal macrophages was found after shock compared to the cells derived from untreated animals (peritoneum: 289 ± 366 ng/ml TNF after shock vs. 2066 ± 94 ng/ml TNF after shock and GM-CSF; lung: 9 ± 12 ng/ml TNF after shock vs. 64 ± 17 ng/ml TNF after shock and GM-CSF; spleen: 58 ± 96 ng/ml TNF after shock vs. 548 ± 47 ng/ml TNF after shock and GM-CSF). Blood cultures collected from rats after hemorrhagic shock did not show a significant increase of TNF-production after GM-CSF treatment.Conclusion: Hemorrhagic shock caused a depression of the TNFa response to LPS which was partly counteracted by treatment with GM-CSF. Therefore, GM-CSF represents a promising approach to normalise trauma- and shock-induced immune dysfunction.Received 4 April 2003; returned for revision 3 July 2003; accepted by A. Falus 25 August 2003     

Statin treatment and a disease-specific pattern of β-amyloid peptides in Alzheimer’s disease

According to the amyloid cascade hypothesis, sporadic Alzheimers disease (AD) is caused by the production and aggregation of -amyloid (A), and the production of A has recently been linked to the metabolism of cholesterol. We have previously published clinical studies where the effect of statin treatment on A production has been investigated. No effect on A was found, which is in disagreement with cell and animal studies. In the present study we investigated the effect of statin treatment on a disease-specific pattern consisting of a C-terminally-truncated quintet of A peptides. Nineteen patients with AD were treated with simvastatin for 12 months and the quintet of A peptides were analysed in cerebrospinal fluid before and after treatment. Also included was a group of 15 untreated patients with AD. We found that the A peptide pattern at baseline was in agreement with earlier findings; however, we did not find any change in the A peptide pattern after statin treatment. We suggest that clinical studies with extended treatment periods are performed where higher dosages of statins are used. We also believe that the pleiotropic effects of statins should be investigated further in order to elucidate the connection between Alzheimers disease and statin treatment.     

Cyclische Nucleotide als intracelluläre Überträgerstoffe bei Hormonwirkungen

Zusammenfassung Hormone dienen als extracelluläre Informationsüberträger zwischen ihrem Bildungsort, einer endokrinen Drüse, und den Zellen, deren Funktion sie regulieren. Durch die Reaktion des Hormons mit den an der Zellmembran gelegenen Receptoren wird die Aktivität der mit diesen eng verknüpften Adenyl-Cyclase beeinflußt. Die meisten Hormone erhöhen in ihrem Zielorgan die Aktivität dieses Enzyms und führen hierdurch zu einem raschen Anstieg der intracellulären Konzentration von Adenosin-3:5-monophosphat (Ado-3:5-P). Dieses cyclische Nucleotid wird durch eine spezifische Phosphodiesterase zu Adenosin-5-monophosphat abgebaut. Auch die Aktivität dieses Enzyms bestimmt die intracelluläre Ado-3:5-P-Konzentration, die im Vergleich zu der anderer Nucleotide sehr gering ist.Ado-3:5-P beeinflußt als zweiter, intracellulärer Überträgerstoff die Aktivität zahlreicher Schlüsselenzyme. Die Ado-3:5-P-Konzentration bestimmt hierdurch das Gleichgewicht verschiedener Stoffwechselwege zueinander und damit die Reaktion einer Zelle auf eine hormonale Stimulierung. An einer Reihe von Enzymen wird die durch Ado-3:5-P bedingte Aktivitäts-Änderung durch einen gleichartigen Mechanismus bewirkt. Das cyclische Nucleotid stimuliert Proteinkinasen, die eine Phosphatgruppe des ATP auf verschiedene Proteine übertragen und hierdurch deren Eigenschaften verändern können. So steigt bei Phosphorylierung durch eine Ado-3:5-P-stimulierbare Proteinkinase die Aktivität der Triglyceridlipase und der Glykogen-Phosphorylase-b-kinase an, dagegen nimmt die Aktivität der Glykogen-Synthetase ab; durch Phosphorylierung von Histonen kann deren Repressorcigenschaft vermindert und die Synthese von Enzymen gesteigert werden.In manchen tierischen Geweben wurde auch eine spezifisch durch Guanosin-3:5-monophosphat (Guo-3:5-P) stimulierbare Proteinkinase nachgewiesen. Dieses cyclische Nucleotid kommt wie Ado-3:5-P in allen Säugerorganen vor. Die Bildung von Guo-3:5-P aus GTP wird durch die Guanyl-Cyclase katalysiert, ein Ferment, das im Gegensatz zur Adenyl-Cyclase zum großen Teil nicht an die Zellmembranen gebunden ist. Die Konzentration von Guo-3:5-P in verschiedenen Geweben, im Blutplasma und im Urin wird durch Hormone beeinflußt. Es ist noch nicht bekannt, welche hormonalen Regulationen durch Guo-3:5-P vermittelt werden; dagegen ist bei vielen, rasch einsetzenden Hormonwirkungen die Beteiligung von Ado-3:5-P nachgewiesen worden.

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Abkürzungen Ado-3:5-P Adenosin-3:5-monophosphat - dAdo-3:5-P Desoxy-adenosin-3:5-monophosphat - Guo-3:5-P Guanosin-3 : 5-monophosphate - Nuc-3:5-P Nucleosid-3:5-monophosphat - NTP Nucleosidtriphosphat - NMP Nuclcosid-5-monophosphat - dATP Desoxyadenosintriphosphat - P_i anorganisches Phosphat - PP_i anorganisches Pyrophosphat - DNS Desoxyribonucleinsäure - RNS Ribonucleinsäure - r-RNS ribosomale RNS - m-RNS Boten-RNS - Glykogen-Synthetase UDP-Glucose--1,4-glucan--4-glucosyltransferase - ICSH interstitial-cell-stimulating hormone     

Expression of estrogen receptors-α and -β in primary breast neoplasms and tumors exposed to neoadjuvant hormonal therapy

We studied the content and expression of mRNA for estrogen receptors receptors- and - in breast tumors before and after 3-month neoadjuvant hormone therapy with antiestrogen tamoxifen and/or aromatase inhibitors. Expression of estrogen receptors- and - was most often detected in ER⁺PR⁺ tumors and most significantly decreased in these neoplasms after exemestane therapy. Immunocytochemical and radioligand assays showed that tamoxifen and anastrozole have little effect on the number of estrogen receptors- The number of progesterone receptors in tumors decreased by the end of anastrozole therapy. Estrogen receptors- were immunocytochemically revealed in 50% primary breast tumors. Anastrozole slightly decreased, while tamoxifen increased the incidence of these receptors. Interruption of signaling through estrogen receptors and suppression of estrogen biosynthesis had different effects on the receptor status of neoplasms and distribution of estrogen receptors- and -.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 11, pp. 559–562, November, 2004     

The effect of central retinal lesions on optokinetic nystagmus in the monkey

Summary In alert monkeys (Macaca mulatta and fascicularis) the effect of central retinal lesions on fast optokinetic responses was investigated during high velocity optokinetic and visual-vestibular conflict stimulation. The fast component of the optokinetic response manifests itself as a rapid rise in the slow-phase eye velocity after light-on, during high velocity optokinetic stimulation; and a sudden drop in eye velocity after light-off. In contrast, the velocity storage component leads only to gradual changes in eye velocity during continuous optokinetic stimulation and after light-off (optokinetic after-nystagmus).Retinal lesions were placed by laser coagulation in and around the fovea. Responses of the normal and lesioned eye were compared. It was found that central lesions up to 12 deg (fovea diameter 6 deg) had only a negligible effect on fast optokinetic responses. With lesions of more than 25–30 deg diameter centered on the fovea definite fast responses could still be obtained, on average reduced to about 50% of the responses of the normal eye. Some monkeys showed initially no fast optokinetic responses and had, therefore, to be excluded from lesion experiments.The results demonstrate that fast optokinetic responses also can be obtained from extrafoveal areas, i.e. areas which are not generally involved in smooth pursuit eye movements. These results are discussed in relation to reports that the smooth pursuit eye movement system is also used to generate fast optokinetic responses.Supported by Swiss National Foundation for Scientific Research 3.343-2.78 and Deutsche Forschungsgemeinschaft, SFB 200 A2These experiments were performed at the Dept. of Neurology, University of Zürich. A preliminary report of this work was presented at the workshop on Physiological and pathological aspects of eye movements in Habay-la-Neuve (Belgium) and at the 8th Extraordinary Meeting of the Barany Society in Basel (Switzerland)     

Effect of resveratrol in experimental osteoarthritis in rabbits

Objective: Resveratrol (trans-3,4,5-trihydroxystilbene) is a phytoalexin found in high concentration in the skins of grapes and red wines which has been shown to have antiinflammatory, anticancerogen and antioxidant properties. Resveratrol is a potent and specific inhibitor of nuclear factor kappa B (NF-B). Resveratrol also inhibits COX-2 gene expression and enzyme activity. We aimed to determine the in vivo effects of intra-articular injections of resveratrol on cartilage and synovium in an experimental osteoarthritis (OA) model in rabbits.Methods: As OA model, rabbits underwent unilateral anterior cruciate ligament transection (ACLT). Five weeks after test group was injected with 10 Mol/kg resveratrol in dimethylsulphoxide (DMSO) in the knees once daily for two weeks and as the control group at the same time DMSO was injected into the knees. All rabbits were killed one week after the last injection. Cartilage tissue and synovium were evaluated with a histological scoring system.Results: Histological evaluation of cartilage tissue by H&E staining revealed a significantly reduced average cartilage tissue destruction score of 1.7 in the resveratrol group versus 2.8 in the control group (p = 0.016). Loss of matrix proteoglycan content in cartilage was also much lower, as determined by safranin O staining. Scores of synovial inflammation didnt show difference between groups (1,3 vs 2,2; p = 0.057).Conclusion: A characteristic parameter in arthritis is the progressive loss of articular cartilage. This study suggests that intraarticular injections of resveratrol starting at the onset of disease may protect cartilage against the development of experimentally induced OA.Received 24 November 2004; returned for revision 29 November 2004; accepted by J. Hamilton 13 December 2004