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PubMed2000

The effect of high-protein diets on coronary blood flow.

Recent research has demonstrated that successful simultaneous treatment of multiple risk factors including cholesterol, triglycerides, homocysteine, lipoprotein (a) [Lp(a)], fibrinogen, antioxidants, endothelial dysfunction, inflammation, infection, and dietary factors can lead to the regression of coronary artery disease and the recovery of viable myocardium. However, preliminary work revealed that a number of individuals enrolled in the original study went on popular high-protein diets in an effort to lose weight. Despite increasing numbers of individuals following high-protein diets, little or no information is currently available regarding the effect of these diets on coronary artery disease and coronary blood flow. Twenty-six people were studied for 1 year by using myocardial perfusion imaging (MPI), echocardiography (ECHO), and serial blood work to evaluate the extent of changes in regional coronary blood flow, regional wall motion abnormalities, and several independent variables known to be important in the development and progression of coronary artery disease. Treatment was based on homocysteine, Lp (a), C-reactive protein (C-RP), triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and fibrinogen levels. Each variable was independently treated as previously reported. MPI and ECHO were performed at the beginning and end of the study for each individual. The 16 people (treatment group/TG) studied modified their dietary intake as instructed. Ten additional individuals elected a different dietary regimen consisting of a "high-protein" (high protein group/HPG) diet, which they believed would "improve" their overall health. Patients in the TG demonstrated a reduction in each of the independent variables studied with regression in both the extent and severity of coronary artery disease (CAD) as quantitatively measured by MPI. Recovery of viable myocardium was seen in 43.75% of myocardial segments in these patients, documented with both MPI and ECHO evaluations. Individuals in the HPG showed worsening of their independent variables. Most notably, fibrinogen, Lp (a), and C-RP increased by an average of 14%, 106%, and 61% respectively. Progression of the extent and severity of CAD was documented in each of the vascular territories with an overall cumulative progression of 39.7%. The differences between progression and extension of disease in the HPG and the regression of disease in the TG were statistically (p<0.001) significant. Patients following recommended treatment for each of the independent variables were able to regress both the extent and severity of their coronary artery disease (CAD), as well as improve their myocardial wall motion (function) while following the prescribed medical and dietary guidelines. However, individuals receiving the same medical treatment but following a high-protein diet showed a worsening of independent risk factors, in addition to progression of CAD. These results would suggest that high-protein diets may precipitate progression of CAI) through increases in lipid deposition and inflammatory and coagulation pathways.

Adult↗

PubMed2004

A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation.

A20 is a stress response gene in endothelial cells (ECs). A20 serves a dual cytoprotective function, protecting from tumor necrosis factor (TNF)-mediated apoptosis and inhibiting inflammation via blockade of the transcription factor nuclear factor-kappaB (NF-kappaB). In this study, we evaluated the molecular basis of the cytoprotective function of A20 in EC cultures and questioned whether its protective effect extends beyond TNF to other apoptotic and necrotic stimuli. Our data demonstrate that A20 targets the TNF apoptotic pathway by inhibiting proteolytic cleavage of apical caspases 8 and 2, executioner caspases 3 and 6, Bid cleavage, and release of cytochrome c, thus preserving mitochondrion integrity. A20 also protects from Fas/CD95 and significantly blunts natural killer cell-mediated EC apoptosis by inhibiting caspase 8 activation. In addition to protecting ECs from apoptotic stimuli, A20 safeguards ECs from complement-mediated necrosis. These data demonstrate, for the first time, that the cytoprotective effect of A20 in ECs is not limited to TNF-triggered apoptosis. Rather, A20 affords broad EC protective functions by effectively shutting down cell death pathways initiated by inflammatory and immune offenders.

Adaptor Proteins, Signal Transducing↗

PubMed2026

One brain, one mind: A joint EPA-EAN leadership perspective on brain health.

Neurology and psychiatry have operated as separate disciplines for over a century, yet this division reflects historical and institutional developments rather than the underlying biology of the brain. Contemporary neuroscience shows that brain and mental health disorders share genetic susceptibilities, inflammatory and metabolic pathways, environmental and social risk factors, and clinical features that cross diagnostic boundaries. Cognitive, emotional, sensory, and motor symptoms regularly appear across both neurological and psychiatric populations, and conditions such as seizures, psychosis, mood disorders, cognitive disorders, and sleep disorders are common to both. A brain health framework addresses this reality by treating the brain as a single biological organ whose function emerges from the interplay between genome and exposome - including stress, trauma, social context, existential meaning, pollution, and physical health - and which underlies perception, behaviour, cognition, emotion, resilience, and vulnerability. Translating this perspective into practice requires coordinated action across domains. Clinically, collaborative models such as joint neurology-psychiatry consultations and shared outpatient pathways can be implemented within existing resources to improve diagnostic clarity and continuity of care. In training, a more harmonised curriculum with shared foundations in neurobiology, joint seminars, and cross-rotations would equip clinicians with a common language while preserving specialist depth, and support the emerging fields of preventive neurology and preventive psychiatry. In research, organising studies around shared mechanisms and symptom dimensions, and launching joint funding calls, would enhance translational relevance and reduce duplication. To realise this vision, sustained leadership from European professional bodies is essential to establish collaboration as a shared professional standard.

Humans↗

PubMed2004

TNFalpha in experimental diseases of the CNS.

Tumor necrosis factor alpha(TNFalpha) is a crucial mediator involved in the communications between immune and nervous systems in physiological conditions, and its relevance is amplified during disease. Considered originally detrimental and a target for therapeutic intervention, recently it has also gained attention for its protective role, especially in central nervous system (CNS) confined diseases. Thus, TNFalpha has become the key molecule illustrating the peculiar and still not completely understood pathways by which inflammatory and immune reactions occur in the brain. Several human pathologies that lack an efficient therapy and that carry enormous social costs rely on these mechanisms. Thus, further research is needed to improve our knowledge and to allow the identification of therapeutic targets or strategies for immune-mediated inflammatory disease of the CNS in which TNFalpha is primarily involved. We describe here how to induce experimental autoimmune encephalomyelitis, cerebral malaria, and brain ischemia in rodents, and some protocols to analyze them. The application of innovative research strategies or original therapeutic approaches to these experimental models may be rewarding in terms of advancement in a field that is crucial for the management of many human patients.

Animals↗

PubMed2004

Familial amyloidotic polyneuropathy: protein aggregation in the peripheral nervous system.

The molecular pathology underlying transthyretin (TTR)-related amyloidosis is largely unknown. It is possible that a common factor in the amyloidogenesis process exists among the different forms; this common factor can involve changes produced by mutations in the three-dimensional structure of TTR, rendering it prone to deposition as amyloid. This amyloidogenic potential, together with other yet unidentified factors, contribute to amyloid deposition. The factors that trigger fibril formation and/or neurodegeneration in TTR-related amyloidosis present central questions for which there are still no available clues. We recently showed in vitro that TTR fibrils trigger NF-kappaB activation, and subsequent studies identified some inflammatory and apoptotic pathways opening perspectives to understand the neurodegeneration process in familial amyloidotic polyneuropathy (FAP). It is current opinion that the modified TTR represents an amyloidogenic intermediate, which integrates the fibril structure; analyses of FAP fibrils have proved that TTR in the fibrils maintains a beta-conformation and have suggested that the TTR monomer is the building block in fibrils. This concept has been questioned recently by investigators, and only future studies on native and synthetic TTR fibrils using high-resolution structural techniques will further elucidate fibril structure and the aggregation pathway. Modulators responsible for phenotypic diversity can be addressed by mice transgenic for different human TTR mutations. Different lines are now available; incomplete penetrance and environmental influence on the deposition of mutant TTR has been observed. Therefore, these animals constitute important tools to address modulators of phenotypic expression and pathophysiological consequences of amyloid deposition at cellular/molecular levels. They are pivotal for testing potential drugs for TTR amyloidosis as well.

Amyloid↗

PubMed2026

Mechanisms by which carbamoylated high-density lipoprotein (C-HDL) promotes calcific aortic valve disease and exploration of potential targeted therapies.

Calcific aortic valve disease (CAVD) is a progressive fibrocalcific illness for which no effective pharmaceutical treatment exists. This study investigated whether carbamoylated high-density lipoprotein (C-HDL), a defective type of HDL that can develop during inflammation, contributes to CAVD progression and the involved molecular pathways. Male ApoE-/- mice were divided into three groups: CAVD model, cyanate-treated, and inhibitor, and analyzed after 12 weeks. C57BL/6 mice on a regular diet served as blank controls. Serum paraoxonase-1 (PON1), aortic valve calcification, cluster of differentiation 31 (CD31), phosphorylated nuclear factor kappa B p65 (p-p65), NOTCH receptor 1 (NOTCH1), and runt-related transcription factor 2 (RUNX2) were evaluated. In parallel, using RNA sequencing (RNA-seq), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, protein-protein interaction (PPI) network analysis, and quantitative real-time polymerase chain reaction. Cyanate treatment reduced serum PON1 levels, increased von Kossa-positive calcium deposition, and raised CD31, p-p65, NOTCH1, and RUNX2 levels compared with the model group, but Gly partially corrected these effects. Transcriptomic research identified 270 C-HDL-associated differentially expressed genes (DEGs) enriched in pathways associated with inflammatory signaling and NF-κB activity. Five potential hub genes (BIRC6, PIK3R1, ATM, IFIH1, and DDX58) were discovered and verified using qRT-PCR. These data show that C-HDL may accelerate CAVD by disrupting valve endothelial homeostasis and stimulating inflammatory signaling, and they identify potential molecular targets for future functional validation.

bioinformatics↗

PubMed2005

Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism.

The epsilon isoform of protein kinase C (PKCepsilon) has emerged as a critical second messenger in sensitization toward mechanical stimulation in models of neuropathic (diabetes, alcoholism, and cancer therapy) as well as acute and chronic inflammatory pain. Signaling pathways leading to activation of PKCepsilon remain unknown. Recent results indicate signaling from cAMP to PKC. A mechanism connecting cAMP and PKC, two ubiquitous, commonly considered separate pathways, remains elusive. We found that, in cultured DRG neurons, signaling from cAMP to PKCepsilon is not mediated by PKA but by the recently identified cAMP-activated guanine exchange factor Epac. Epac, in turn, was upstream of phospholipase C (PLC) and PLD, both of which were necessary for translocation and activation of PKCepsilon. This signaling pathway was specific to isolectin B4-positive [IB4(+)] nociceptors. Also, in a behavioral model, cAMP produced mechanical hyperalgesia (tenderness) through Epac, PLC/PLD, and PKCepsilon. By delineating this signaling pathway, we provide a mechanism for cAMP-to-PKC signaling, give proof of principle that the mitogen-activated protein kinase pathway-activating protein Epac also stimulates PKC, describe the first physiological function unique for the IB4(+) subpopulation of sensory neurons, and find proof of principle that G-protein-coupled receptors can activate PKC not only through the G-proteins alpha(q) and betagamma but also through alpha(s).

Animals↗

PubMed2003

Autoimmunity in the peripheral nervous system.

Autoimmune disorders of the peripheral nervous system (PNS) comprise a heterogeneous group of diseases that result from an aberrant immune response. Most of these disorders present severe morbidity and, in some cases, mortality. Even those conditions that are self-limited may display severe disability and necessitate hospitalization. Although their etiology remains elusive, there is increasing knowledge of the pathophysiological mechanisms causing tissue dysfunction and structural damage. The discovery of several mediators that constitute the molecular mechanisms of cell-cell and cell-extracellular-matrix interactions has revealed insight into various aspects of the neuroimmune interaction. Classic animal models associated with new genetic approaches have further increased our comprehension of the molecular pathways that regulate inflammatory disorders of the nervous system. The aim of this review is to describe various types and functions of the principal molecular components of the neuroimmune interaction and their importance in the principal autoimmune disorders of the PNS. We also provide an extensive description of clinical and pathological features of autoimmune disorders of the PNS, along with diagnostic and therapeutic implications.

Animals↗

PubMed1988

Perspectives in corticosteroid research.

In dermatotherapy, potent drugs are needed which can be used as alternatives to corticosteroids, but which are without unwanted local and systemic effects. Three theoretical possibilities for the development of such advanced drugs have been presented. Firstly, dissociation of wanted and unwanted effects by selection of a certain corticosteroid structure is proposed. However, this is impossible, because corticosteroid receptors are ubiquitous and all display the same specificity. Secondly, manipulation of the pathways of the inflammatory response may be more feasible. Because of increasing knowledge of the mechanism of inflammation and the pathogenesis of cutaneous inflammatory diseases, it is predictable that effective nonsteroidal anti-inflammatory drugs for topical use will be developed some time in the future. Lastly, the effects and side effects can now be limited to the site of application, thus avoiding systemic risks, by optimising corticosteroid activity with respect to receptor binding and pharmacokinetic properties. However, it is realistic to assume that, even in the future, corticosteroids will always possess both desirable and undesirable properties.

Administration, Topical↗

PubMed2005

Pathway proteomics: global and focused approaches.

Biological pathways represent the relationships (reactions and interactions) between biological molecules in the context of normal cellular functions and disease mechanisms. Understanding the roles of proteins and signaling pathways expressed within disease, and their link to drug discovery and drug development are central in today's target-driven pharmaceutical processes. This article gives an overview of proteomics strategies, including global expression analysis as well as focused approaches using multidimensional separation by both gel- and liquid-phase techniques linked to mass spectrometry, as applied to two of the pathways involved in inflammatory diseases. In primary human cell studies, our group has annotated and identified thousands of proteins using both electrospray ionization and matrix-assisted laser desorption ionization (MALDI)-sequencing technology. Annotations made from gel images and chromatography fractionation, interfaced to high-end mass spectrometry sequence and structure identity, are cornerstones in cutting-edge protein expression profiling. Regarding phosphorylation mechanisms of kinases, the quantitative stoichiometry can be determined using affinity probe isolations. Another strategy involves micro-preparative sample processing, which has been used to analyze single-target phosphoproteins and their relative phospho-stoichiometry.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2005

A role for the complement system in rheumatoid arthritis.

The production of autoreactive antibodies from self-reactive B cells results in the formation of immune complexes that deposit in tissue and fix complement, contributing to the pathogenesis of rheumatoid arthritis (RA). Earlier mouse models emphasize the importance of autoreactive antibodies formed against "self" proteins that serve as a source for T cell-mediated immune response, stemming from cross-reactivity and resulting in B cell activity. However, more recent models suggest the need for both autoantibodies and the initiation of the inflammatory cascade via the alternative complement pathway, which is unbridled as the cartilage lacks the usual regulatory proteins of the complement system. Furthermore, deficiencies in specific complement proteins could lead to an escape from negative selection by these self-reactive B cells. Moreover, the classical complement pathway establishes chemotactic gradients by which inflammatory cells follow and accumulate in the synovial fluid where they engulf immune complexes and release proteolytic enzymes. In addition, the processing of circulating immune complexes either via Fc receptor or CR1 and opsonization by complement fragments plays a key role in determining the fate of immune status. In addition, complement proteins are a major determinant in the size and solubility of an immune complex, which also affects clearance. The evidence regarding intra-articular activation of the complement system in RA provides the possibility to pharmacologically manipulate various parts of the complement system for therapeutic purposes and potential therapeutic targets for the control of inflammation and the prevention of joint destruction.

Animals↗

PubMed2005

Therapeutic chelators for the twenty first century: new treatments for iron and copper mediated inflammatory and neurological disorders.

Superoxide, hydrogen peroxide, hydroxyl radicals and peroxynitrite are collectively termed reactive oxygen and nitrogen species (RONS). They have been ascribed an important role in oxidative stress contributing to the progression of inflammatory diseases. RONS generating systems include the inflammatory response, enzymatic pathways and as side products of catabolism. Protective enzymes exist for the regulation of RONS such as superoxide dismutase, catalase and glutathione peroxidase. Furthermore, vitamins play a secondary role in deactivating RONS. The redox active metal ions such as ferrous and cuprous ions are released from the storage proteins ferritin and caeruloplasmin by RONS. Redox active metal ions further activate/generate RONS and thus perpetuate their damaging effects. Here we report recent therapies that focus on intervening in the roles of metal ions in oxidative stress. These include: i) chelators which complex labile metal ions to form antioxidant enzyme mimetics, ii) site-specific RONS scavengers, where dual functionality co-localizes the scavenger and chelation centre to direct scavenging, and iii) redox silencing, metal complexation with concomitant stabilization of the metal ion in the oxidized form to prevent further activation of RONS. The rationale for this new therapeutic approach and recent advances will be presented in this review.

Chelating Agents↗

PubMed2004

Evidence for vascular and enzymatic events in the pathophysiology of acute laminitis: which pathway is responsible for initiation of this process in horses?

To date, there is a substantial amount of data to support the hypotheses that vascular and enzymatic changes are ongoing in experimental laminitis. Furthermore, there is substantial in vitro evidence that the enzymatic changes weaken the dermo-epidermal attachments leading to mechanical failure of the hoof-bone interface of the equine digit. However, investigators of both the vascular and enzymatic theories have, to date, been unable to substantiate the effects of these pathophysiological changes in vivo on laminar tissues of horses afflicted with experimentally induced or naturally acquired laminitis. In addition, the effects of laminitis-inducing treatment have not been prevented or reversed by treatment with an MMP inhibitor or a vasoactive antagonist. It is possible that there is simultaneous activation of the vascular and enzymatic pathways and/or other inflammatory processes. Moreover, the third theory involving mechanical factors cannot be discounted simply because strong evidence for vascular and enzymatic changes exists. It is common for horses with severe musculoskeletal disease affecting weightbearing on a limb to develop laminitis in the contralateral limb. It remains to be determined what factors are responsible for initiation of laminitis in these individuals. Evidence has not been presented that precludes the possibility of coincident occurrence of vascular and enzymatic changes. In fact, many of the inflammatory mediators (e.g. interleukin-1beta) found in laminitic tissues can concurrently stimulate synthesis of vasoactive substances and activate MMPs. Because enzymatic action on proteins is largely dependent on the concentrations of proteins and enzyme, the enzymatic theory is not dependent upon increased delivery of enzymes via increased capillary flow. Likewise, because vascular changes can alter tissue function via increased capillary flow and oedema formation, the vascular theory is not dependent upon decreased capillary flow. It is true that naturally acquired laminitis is widely variable in severity and predisposing diseases. Therefore, most probably there are multiple mechanisms involved in the initiation and propagation of the pathophysiologic cascade(s) and, therefore, successful intervention will necessitate multiple treatment modalities.

Acute Disease↗

PubMed2026

Aqueous humour extracellular vesicle membrane protein profiling reveals pathological features of refractory macular edema.

BACKGROUND: Both diabetic macular edema (DME) and retinal vein occlusion-related macular edema (RVO-ME) can become refractory to anti-vascular endothelial growth factor (anti-VEGF) therapy, but the underlying mechanisms are unclear. Molecular discrimination of refractory disease could guide personalized treatment. This study examined whether aqueous humor-derived extracellular vesicle (EV) membrane proteins can characterize refractoriness and reveal etiology-specific pathways. METHODS: This prospective cohort study included 28 patients with DME or RVO-ME (14 each), further divided into treatment-naïve and refractory subgroups. Aqueous humour samples were collected before intravitreal anti-VEGF injection. EV membrane proteins were profiled using an EV Array chip targeting 435 antibodies. Differentially expressed proteins were analyzed by bioinformatics, including Gene Ontology, Kyoto encyclopaedia of genes and genomes (KEGG) pathway enrichment, Gene set enrichment analysis (GSEA), and cell-of-origin mapping using public single-cell RNA-seq data. RESULTS: VEGF/VEGFR2 were elevated in treatment-naïve DME and RVO-ME. Refractory DME showed upregulation of C5 and CD34 (complement/immune activation). Refractory RVO-ME exhibited increased CD68 and Annexin A1 with decreased PDGFR (chronic inflammation, vascular dysregulation). RANTES was commonly upregulated in refractory disease. Several EV proteins discriminated refractory cases with high accuracy (AUC 0.898-0.980). Cellular origin suggested immune cell-derived EVs in DME, retinal cell-derived EVs in RVO-ME. External validation confirmed key differences. CONCLUSION: Refractory ME involves distinct pathways: immune-inflammatory activation in DME versus chronic inflammation with vascular dysregulation in RVO-ME. EV membrane proteins from aqueous humor provide insights into therapeutic resistance and hold promise as biomarkers for personalized treatment decisions.

artificial intelligence↗

PubMed2006

The relationship between inflammation and the coagulation system.

Inflammation and coagulation play pivotal roles in host defence. As phylogenetically old responses, there is extensive cross-talk between inflammation and coagulation in enabling an adequate immune response against potentially injurious stimuli. Immune cells are important in the initiation of coagulation pathways, while various inflammatory mediators are capable of altering haemostasis. Vice versa, coagulation proteases have significant immunomodulatory effects. Understanding the mechanisms involved in the crosstalk between inflammation and coagulation may yield new therapeutic strategies for human diseases.

Blood Coagulation↗

PubMed2000

Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy.

BACKGROUND: Several studies have indicated that estrogen may prime inflammatory and nociceptive pathways, leading to symptoms that mimic cholecystitis. We set out to confirm the relation between recent estrogen use and cholecystectomy in postmenopausal women and to test the novel hypothesis that a similar relation exists for appendectomy. METHODS: We developed a retrospective cohort using prescribing and surgical procedure information from health administrative databases for approximately 800,000 female residents of Ontario who were over 65 years of age between July 1, 1993, and Mar. 31, 1998. We compared the incidence of cholecystectomy and appendectomy among women recently prescribed estrogen replacement therapy, levothyroxine and dihydropyridine calcium-channel antagonists (DCCA) using age-adjusted Cox proportional hazards models. Patients were followed for a mean of 540 (standard deviation [SD] 449) days. RESULTS: Compared with women taking DCCA, those who had recently begun taking estrogen were significantly more likely to undergo cholecystectomy (age-adjusted risk ratio [aRR] 1.9, 95% confidence interval [CI] 1.6-2.2) and appendectomy (aRR 1.8, 95% CI 1.1-3.0). No significant difference in either outcome measure was found between the levothyroxine users and the DCCA users. INTERPRETATION: This study identifies an increased risk of cholecystectomy and appendectomy among postmenopausal women who have recently begun estrogen replacement therapy.

Aged↗

PubMed2000

Serum-induced monocyte differentiation and monocyte chemotaxis are regulated by the p38 MAP kinase signal transduction pathway.

Regulation by the p38 mitogen-activated protein (MAP) kinase signaling pathway of monocytic inflammatory functions was evaluated using L-790,070, a potent and selective inhibitor of p38 MAP kinase. Three major functions of monocytes were investigated: differentiation, chemotaxis, and phagocytosis. L-790,070 inhibited serum-induced monocyte differentiation with an IC50 of 0.5 nM. Monocyte chemotaxis induced by RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemotactic protein- (MCP-1), and fMLP were all sensitive to L-790,070. When titrated, L-790,070 inhibited MCP-1-induced chemotaxis in a concentration-dependent manner with an IC50 of 0.3 nM. However, the ability of serum-derived macrophages to phagocytose apoptotic neutrophils was unaffected by L-790,070. The concentration with which L-790,070 inhibited both differentiation and chemotaxis was similar to that necessary to inhibit p38 MAP kinase activation of MAPKAP kinase (0.3 nM) in response to stimulation by lipopolysaccharide. Therefore, the data in this report suggest that the mechanism by which L-790,070 blocked monocyte differentiation and prevented chemotaxis was by inhibiting p38 MAP kinase activity.

Adult↗

PubMed2000

Effective adenoviral transfer of IkappaBalpha into human fibroblasts and chondrosarcoma cells reveals that the induction of matrix metalloproteinases and proinflammatory cytokines is nuclear factor-kappaB dependent.

OBJECTIVE: To determine whether, in human fibroblasts and chondrosarcoma cells, the regulation of interleukins (IL)-6, 8, and 11 and matrix metalloproteinases (MMP)-1, 3, and 13, and their tissue inhibitor TIMP-1, depends on the transcription factor nuclear factor-kappaB (NF-kappaB). METHODS: Fibroblasts and chondrosarcoma cells were effectively infected with an adenovirus encoding human IkappaBalpha, and inhibition of NF-kappaB function was observed. The induction of MMP and IL-6, 8, and 11 by various stimuli was assessed by ELISA. RESULTS: The induction of IL-6 and IL-8 clearly depended on NF-kappaB in both fibroblasts and chondrosarcoma cells, irrespective of stimulus, but IkappaBalpha overexpression had little effect on IL-11. MMP-1, -3, and -13 were also inhibited, but TIMP-1 was unaffected. CONCLUSION: NF-kappaB appears to play an important and selective role in MMP induction in human fibroblasts and chondrosarcoma cells. This suggests there are NF-kappaB dependent mechanisms of cartilage destruction in rheumatoid arthritis, and supports the concept that there are similarities in the regulation of inflammatory and destructive pathways in that disease.

Arthritis, Rheumatoid↗