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PubMed2005

Bile acid signaling through FXR induces intracellular adhesion molecule-1 expression in mouse liver and human hepatocytes.

Previous studies have demonstrated a dramatic induction of inflammatory gene expression in livers from mice fed a high-fat, high-cholesterol diet containing cholate after 3-5 wk. To determine the contribution of cholate in mediating these inductions, C57BL/6 mice were fed a chow diet supplemented with increasing concentrations of cholic acid (CA) for 5 days. A dose-dependent induction in the hepatic levels of TNF-alpha, VCAM-1, ICAM-1, and SAA-2 mRNA were observed. As positive controls, a dose-dependent repression of cholesterol 7alpha-hydroxylase and a dose-dependent induction of small heterodimer partner (SHP) expression were also observed, suggesting that farnesoid X receptor (FXR) was activated. In addition, ICAM-1 and SHP mRNA levels were also induced in primary human hepatocytes when treated with chenodeoxycholic acid or GW4064, a FXR-selective agonist. The involvement of FXR in CA-induced inflammatory gene expression was further investigated in the human hepatic cell line HepG2. Both ICAM-1 and SHP expression were induced in a dose- and time-dependent manner by treatment with the FXR-selective agonist GW4064. Moreover, the induction of ICAM-1 by GW4064 was inhibited by the FXR antagonist guggulsterone or with transfection of FXR siRNA. Finally, the activity of FXR was mapped to a retinoic acid response element (RARE) site containing an imbedded farnesoid X response element (FXRE) on the human ICAM-1 promoter and FXR and retinoid X receptor were demonstrated to bind to this site. Finally, FXR-mediated activation of ICAM-1 could be further enhanced by TNF-alpha cotreatment in hepatocytes, suggesting a potential cooperation between cytokine and bile acid-signaling pathways during hepatic inflammatory events.

Animals↗
PubMed1999

RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.

S100/calgranulin polypeptides are present at sites of inflammation, likely released by inflammatory cells targeted to such loci by a range of environmental cues. We report here that receptor for AGE (RAGE) is a central cell surface receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Blockade of EN-RAGE/RAGE quenches delayed-type hypersensitivity and inflammatory colitis in murine models by arresting activation of central signaling pathways and expression of inflammatory gene mediators. These data highlight a novel paradigm in inflammation and identify roles for EN-RAGEs and RAGE in chronic cellular activation and tissue injury.

Amino Acid Sequence↗
PubMed1999

Host responses to secreted Shigella virulence factors.

Shigella and related enteropathogens deliver effector molecules into the cytoplasm of epithelial cells and macrophages via a type III secretion system. Epithelial cells respond to contact with Shigella by rearranging the cytoskeleton, which leads to uptake of the bacterium. Apart from several cytoskeletal proteins, this process involves the recruitment and activation of kinases, and the small GTPase rho. Macrophages infected with Shigella undergo apoptosis and release mature IL-1beta, a pro-inflammatory cytokine. This apoptotic pathway requires caspase-1 (IL-1beta-converting enzyme). Pro-inflammatory macrophage apoptosis triggers acute shigellosis and might be relevant in other infectious diseases.

Journal Article↗
PubMed2006

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling.

Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. Using expression microarrays and a unique method for comparative expression analysis called L2L, we sought to define this defect in cells lacking a functional CS group B (CSB) protein, the SWI/SNF-like ATPase responsible for most cases of CS. Remarkably, many of the genes regulated by CSB are also affected by inhibitors of histone deacetylase and DNA methylation, as well as by defects in poly(ADP-ribose)-polymerase function and RNA polymerase II elongation. Moreover, consistent with these microarray expression data, CSB-null cells are sensitive to inhibitors of histone deacetylase or poly(ADP-ribose)-polymerase. Our data indicate a general role for CSB protein in maintenance and remodeling of chromatin structure and suggest that CS is a disease of transcriptional deregulation caused by misexpression of growth-suppressive, inflammatory, and proapoptotic pathways.

Cell Line↗
PubMed2006

Nucleotide metabolism and cell-cell interactions.

Interactions between the vascular endothelium and polymorphonuclear leukocytes (PMNs) are central to PMN emigration into inflamed tissues, and to neutrophil-endothelial crosstalk pathways that modulate inflammatory responses and vascular barrier function. For example, during episodes of inflammation, the transendothelial migration (TEM) of PMNs potentially disturbs vascular barrier and gives rise to intravascular fluid extravasation and edema. However, because of the close special relationship between PMNs and the vascular endothelium, TEM creates an ideal situation for neutrophil-endothelial crosstalk. While investigating innate mechanisms to dampen intravascular fluid loss and edema occurring during TEM, we observed that PMNs release adenine nucleotides after activation (adenosine triphosphate [ATP] and adenosine monophosphate [AMP]). ATP and AMP are metabolized by endothelial cell-surface enzymes, the ecto-apyrase (CD39, metabolizes ATP to AMP) and the 5'-ecto-nucleotidase (CD73, metabolizes AMP to adenosine). Adenosine generated in this fashion can activate endothelial adenosine receptors, leading to increases in intracellular cyclic AMP and resealing of the endothelial junctions, thereby promoting vascular barrier function. This crosstalk pathway provides an endogenous mechanism to dampen vascular leak syndrome during neutrophil-endothelial interaction. In other words, during TEM, neutrophils close the door behind them.

5'-Nucleotidase↗
PubMed2005

The emerging role of adipocytokines as inflammatory mediators in inflammatory bowel disease.

Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD.

Adipocytes↗
PubMed2006

Hsp70 inhibits lipopolysaccharide-induced NF-kappaB activation by interacting with TRAF6 and inhibiting its ubiquitination.

Inducible heat shock protein 70 (Hsp70) is one of the most important HSPs for maintenance of cell integrity during normal cellular growth as well as pathophysiological conditions. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a crucial signaling transducer that regulates a diverse array of physiological and pathological processes and is essential for activating NF-kappaB signaling pathway in response to bacterial lipopolysaccharide (LPS). Here we report a novel mechanism of Hsp70 for preventing LPS-induced NF-kappaB activation in RAW264.7 macrophage-like cells. Our results show that Hsp70 can associate with TRAF6 physically in the TRAF-C domain and prevent TRAF6 ubiquitination. The stimulation of LPS dissociates the binding of Hsp70 and TRAF6 in a time-dependent manner. Hsp70 inhibits LPS-induced NF-kappaB signaling cascade activation in heat-shock treated as well as Hsp70 stable transfected RAW264.7 cells and subsequently decreases iNOS and COX-2 expression. Two Hsp70 mutants, Hsp70DeltaC(1-428aa) with N-terminal ATPase domain and Hsp70C(428-642aa) with C-terminal domain, lack the ability to influence TRAF6 ubiquitination and TRAF6-triggered NF-kappaB activation. Taken together, these findings indicate that Hsp70 inhibits LPS-induced NF-kappaB activation by binding TRAF6 and preventing its ubiquitination, and results in inhibition of inflammatory mediator production, which provides a new insight for analyzing the effects of Hsp70 on LPS-triggered inflammatory signal transduction pathways.

Animals↗
PubMed2001

Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury.

BACKGROUND & AIMS: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury. METHODS: PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed. RESULTS: In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway. CONCLUSIONS: These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.

Animals↗
PubMed2003

Connective molecular pathways of experimental bladder inflammation.

Inflammation is an inherent response of the organism that permits its survival despite constant environmental challenges. The process normally leads to recovery from injury and to healing. However, if targeted destruction and assisted repair are not properly phased, chronic inflammation can result in persistent tissue damage. To better understand the inflammatory process, we recently introduced a profiling methodology to identify common genes involved in bladder inflammation. The method represents a complementation to the classic quantification of inflammation and provides information regarding the early, intermediate, and late events in gene regulation. However, gene profiling fails to describe the molecular pathways and their interconnections involved in the particular inflammatory response. The present work introduces a new statistical technique for inferring functional interconnections between inflammatory pathways underlying classic models of bladder inflammation and permits the modeling of the inflammatory network. This new statistical method is based on variants of cluster analysis, Boolean networking, differential equations, Bayesian networking, and partial correlation. By applying partial correlation analysis, we developed mosaics of gene expression that permitted a global visualization of common and unique pathways elicited by different stimuli. The significance of these processes was tested from both biological and statistical viewpoints. We propose that connective mosaic may represent the necessary simplification step to visualize cDNA array results.

Animals↗
PubMed2006

Changes in synovial tissue Jak-STAT expression in rheumatoid arthritis in response to successful DMARD treatment.

BACKGROUND: Modulation of Jak-STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA). OBJECTIVE: To examine the effect of successful disease-modifying antirheumatic drug (DMARD) treatment on the expression of Jak-STAT in a cohort of patients with active rheumatoid arthritis. METHODS: Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry. RESULTS: Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation. CONCLUSION: Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up-regulation of inhibitory pathways, or suppressing inflammatory paths.

Antirheumatic Agents↗
PubMed2002

High-efficiency gene transfer into nontransformed cells: utility for studying gene regulation and analysis of potential therapeutic targets.

The elucidation of the signalling pathways involved in inflammatory diseases, such as rheumatoid arthritis, could provide long sought after targets for therapeutic intervention. Gene regulation is complex and varies depending on the cell type, as well as the signal eliciting gene activation. However, cells from certain lineages, such as macrophages, are specialised to degrade exogenous material and consequently do not easily transfect. Methods for high-efficiency gene transfer into primary cells of various lineages and disease states are desirable, as they remove the uncertainties associated with using transformed cell lines. Significant research has been undertaken into the development of nonviral and viral vectors for basic research, and as vehicles for gene therapy. We briefly review the current methods of gene delivery and the difficulties associated with each system. Adenoviruses have been used extensively to examine the role of various cytokines and signal transduction molecules in the pathogenesis of rheumatoid arthritis. This review will focus on the involvement of different signalling molecules in the production of tumour necrosis factor alpha by macrophages and in rheumatoid synovium. While the NF-kappaB pathway has proven to be a major mediator of tumour necrosis factor alpha production, it is not exclusive and work evaluating the involvement of other pathways is ongoing.

Animals↗
PubMed2005

Gene expression changes in leukocytes during cardiopulmonary bypass are dependent on circuit coating.

BACKGROUND: Cardiopulmonary bypass (CPB) results in a systemic inflammatory response. Leukocytes play a crucial role in inflammatory reactions. Their gene expression profile in the context of CPB is unknown. METHODS AND RESULTS: In a prospective, randomized, and double-blind clinical trial, 12 male patients underwent elective coronary artery bypass grafting with either heparin-coated (group H) or protein-coated (group P) CPB circuits. Oligonucleotide microarray analyses of 22,283 genes were performed on circulating leukocytes, collected immediately before surgery and 6 hours after CPB. Microarray results were validated with real-time polymerase chain reaction. All patients had uneventful surgery, and no significant differences between groups were observed during the clinical course. Multiple statistical analyses with different methods were performed. Compared with preoperative expression at a threshold value of P<0.01, postoperative expression revealed 814 upregulated and 1187 downregulated genes in group H compared with 99 upregulated and 231 downregulated in group P (P<0.001). Fifty genes exhibited a >4-fold increase and 27 exhibited a >4-fold decrease in group H, whereas only 7 genes exhibited upregulation and 7 revealed downregulation in group P. Microarray-pathway-profile-finder analyses determined 1405 upregulated and 1454 downregulated pathways in group H compared with 552 upregulated and 818 downregulated pathways in group P (P<0.01). Pathways related to inflammatory response exhibited highest z scores in group H, reflecting cellular inflammatory activation. CONCLUSIONS: Heparin coating resulted in a more profound alteration in leukocyte gene expression when compared with protein coating. Microarray analyses present an innovative approach for the evaluation and understanding of inflammatory reactions associated with CPB.

Aged↗
PubMed2002

Oxidized phospholipids inhibit cyclooxygenase-2 in human macrophages via nuclear factor-kappaB/IkappaB- and ERK2-dependent mechanisms.

OBJECTIVE: Oxidized low-density lipoproteins (ox-LDL) or their components suppress macrophage inflammatory response by down-regulating cytokine synthesis, nitric oxide synthase and inducible cyclooxygenase (Cox-2). This event is crucial for the pathophysiological process leading to the formation of atherosclerotic plaque. Our present study focused on the mechanisms through which oxidized phospholipids inhibit LPS-induced Cox-2 expression in human macrophages. METHODS: Macrophages were incubated with a mixture of oxidized fragmented phospholipids (ox-PAPC), present in modified LDL, and then exposed to LPS. Cox-2 was evaluated in terms of protein levels, mRNA and activity. RESULTS: Ox-PAPC dose-dependently inhibited Cox-2 protein, mRNA and activity by preventing NF-kappaB binding to DNA. This effect was consequent to alterations of the degradation pattern of IkappaBalpha. Moreover, ox-PAPC markedly prevented extracellular signal-regulated kinase (ERK2) activation, leading to Cox-2 expression, whereas activation of the transcription factor peroxisome proliferator-activated receptors (PPARs) was not influenced. CONCLUSION: ox-PAPC down-regulates LPS-induced Cox-2 expression in human macrophages by targeting both NF-kappaB/IkappaB and ERK2 pathways. An altered inflammatory response by macrophages within atheromata may contribute to the progression of atherosclerosis.

Cell Culture Techniques↗
PubMed1997

Alkali burn-induced synthesis of inflammatory eicosanoids in rabbit corneal epithelium.

PURPOSE: Alkali burning of the rabbit cornea is a well-established model for the study of anterior surface inflammation, neovascularization, and wound-healing processes. 12-hydroxyeicosanoids have been implicated as mediators of such responses. 12(S)-hydroxyeicosatetraenoic acid (12[S]-HETE) is a lipoxygenase-derived arachidonate metabolite and 12(R)-hydroxyeicosatetraenoic acid (12[R]-HETE) is formed by a cytochrome P450 monooxygenase; both give rise to the potent angiogenic factor 12(R)-hydroxyeicosatrienoic acid (12[R]-HETrE). In this study, the authors correlate the pattern of their synthesis in the corneal epithelium with the inflammatory response after alkali injury. METHODS: New Zealand albino rabbits were anesthetized and alkali burns created with 10-mm filter paper discs (1 N NaOH for 2 minutes). Corneas were then rinsed; 1 to 7 days later, corneal epithelium was scraped and used to assess 14C-arachidonic acid conversion to 12-HETE and 12-HETrE enantiomers in the presence of NADPH by chiral high-pressure liquid chromatography. The inflammatory response secondary to the alkali burn was quantified through area measurements of reepithelialization and neovascularization. RESULTS: Alkali burn induced a time-dependent production of corneal epithelial 12-HETE and 12-HETrE. A marked increase in 12-HETE and 12-HETrE synthesis was evident at day 2 (from 22 +/- 7 to 139 +/- 22 ng/hour) after injury, increasing to 800 +/- 68 ng/hour at day 7. Chiral analysis revealed a time-dependent synthesis of the R and S enantiomers of 12-HETE (24% R, 76% S) and 12-HETrE (72% R, 28% S). Total arachidonate metabolism, as well as the formation of 12(R)-HETrE, correlated with the area of neovascularization (P < 0.01 and P < 0.02, respectively). CONCLUSIONS: The results demonstrate that surviving and regenerating epithelium has an increased capacity of synthesizing 12(S)-HETE and 12(R)-HETE and that maximal production of 12(R)-HETrE, a known direct and indirect angiogenic factor, coincides with neovascularization in this model. Thus, the lipoxygenase and cytochrome P450-dependent activities increased in a time-dependent manner, indicating the potential involvement of both pathways in the inflammatory response to alkali burn. The formation of significant quantities of 12(R)-HETE and 12(R)-HETrE is a novel finding in this alkali injury model.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2005

Preconditioning of primary human endothelial cells with inflammatory mediators alters the "set point" of the cell.

Endothelial cells are highly sensitive to changes in the extracellular milieu. Sepsis results in activation of inflammatory and coagulation pathways. We hypothesized that sepsis-associated mediators may alter the response capacity (so-called "set point") of endothelial cells. Human umbilical vein endothelial cells (HUVEC) were preincubated in the presence or absence of tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), hypoxia, hyperthermia, and/or high glucose; treated with or without thrombin for 4 h; and then processed for RNase protection assays of selected activation markers. Priming with TNF-alpha and LPS significantly inhibited thrombin-mediated induction of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tissue factor, and E-selectin, but not platelet-derived growth factor-A or CD44. In electrophoretic mobility shift assays, thrombin-treated HUVEC demonstrated inducible binding of p65 NF-kappaB, an effect that was significantly blunted by pretreatment of cells with TNF-alpha and LPS. Consistent with these results, TNF-alpha and LPS attenuated the effect of thrombin on IkappaB phosphorylation, total cytoplasmic IkappaB, and nuclear translocation of p65 NF-kappaB. The inhibitory effect of TNF-alpha on thrombin signaling persisted for up to 24 h following removal of the cytokine. Taken together, these data suggest that inflammatory mediators prime endothelial cells to modulate subsequent thrombin response.

Active Transport, Cell Nucleus↗
PubMed2003

NF-kappaB in cultivated middle ear epithelium.

OBJECTIVE: Otitis media with effusion (OME) may develop into a chronic course in some patients. In the majority of cases lipopolysaccharide (LPS) is detected in the middle ear fluid being capable of initiating and maintaining the inflammatory process associated with the disease. In addition, various extracellular signs of the inflammatory cascade are present, such as cytokines and ICAM-1 receptors. However, the underlying regulatory mechanisms situated intracellularily are sparsely recognized. NF-kappaB is a ubiquitously transcription factor complexed to its inhibitor within the cytoplasm. In response to stimuli, e.g. LPS or cytokines, NF-kappaB becomes activated and is translocated to the nucleus. At this level it induces transcription of various genes and subsequent expression of mRNA encoding for many immunoglobulins and cytokines, e.g. interleukin 8 (IL-8) which may be responsible for prolonging and maintaining the inflammatory process. METHODS: To evaluate if NF-kappaB is present in middle ear epithelium including to identify possible stimulating factors in vitro studies using rabbit middle ear epithelial cells (meec) were undertaken. Both normal cells and LPS exposed cells were studied. ELISA techniques were applied to detect NF-kappaB, ICAM-1 receptors and IL-8. All measurements were adjusted to the concentration of total cell protein (TP). RESULTS: NF-kappaB was detected in the normal middle ear epithelium in concentrations between 16.8 and 28.6 ng/microg TP. In response to LPS the NF-kappaB content increased with 25-33%. This enhancement became more pronounced with longer duration of the LPS exposition. A relatively distinct expression of ICAM-1 preceded the NF-kappaB increase, after which the ICAM-1 measurements declined. IL-8 was hardly measurable in normal cells. The IL-8 concentrations were higher in LPS exposed cultures. The time related curve demonstrated a diphasic shape with an early and a late maximum. CONCLUSION: The chronic inflammation seen in some OME patients may be due to LPS activating ICAM-1 receptors and NF-kappaB followed by release of IL-8. An autocrine pathway may be established through activation of TNF alpha and IL-1beta. Thus, elucidation of alternative pathways in the inflammatory cascade and elimination of LPS, alternatively inhibition of NF-kappaB and/or IL-8, should be an issue for future investigation.

Animals↗
PubMed1996

Suppression of inflammatory arthritis by simultaneous inhibition of nitric oxide synthase and NADPH oxidase.

TH1-type proinflammatory cytokines induce the expression of phagocytic nitric oxide synthase (NOS) and prime the membrane-bound NADPH oxidase of neutrophils and monocytes of mice so as to attain an activated state, which upon a second stimulus releases up to 6-fold increased levels of reactive oxygen species (ROS) than do unprimed phagocytes. Enhanced levels of ROS and NO deregulate inflammatory signal transduction pathways, which play a crucial role in the pathogenesis of arthritis. The antiarthritic reactivity of diphenylene iodoniumchloride (DPI), an irreversible inhibitor of NADPH oxidase and NOS, was tested in male DBA/1xB10A(4R) hybrid mice suffering from potassium peroxochromate-induced arthritis. Daily doses of 2.8 mu mol/kg of DPI sufficed to inhibit the arthritis by 50%. A complete inhibition was obtained with 10 mu mol/kg of DPI. The reduction of overt arthritic symptoms correlated well with both the reduced levels of ROS and NO in plasma of DPI-treated mice. Our data support the hypothesis that oxidative stress and nitric oxides play a pivotal role in the pathology of arthritis, which can be therapeutically targetted by NADPH oxidase- and NO synthase-inhibitors.

Animals↗
PubMed1999

Tumor necrosis factor-alpha and the progression of diabetes in non-obese diabetic mice.

In the past decade, a wealth of information has accumulated through studies in non-obese diabetic (NOD) mice regarding the molecular and cellular events that participate in the progression to diabetes in insulin-dependent diabetes mellitus (IDDM). One molecule that has received considerable attention is the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). TNF-alpha has been demonstrated to have a positive or negative effect on the progression to diabetes in NOD mice, although the mechanism by which TNF-alpha exerts these differential outcomes is unknown. Here we describe a new NOD model for analyzing the role of TNF-alpha in IDDM, TNF-alpha-NOD mice. TNF-alpha-NOD mice express TNF-alpha solely in their islets from neonatal life onwards, and develop accelerated progression to diabetes. This rapid progression to diabetes is related to earlier and more aggressive infiltration of the islets with immune cells and an enhancement in the presentation of islet antigen in situ in the islets by islet-infiltrating antigen-presenting cells to T cells. Although adoptive transfer studies demonstrated that TNF-alpha can enhance presentation of islet antigen to both effector CD4+ and CD8+ T cells, further investigations in TNF-alpha-NOD mice deficient in either CD4+ or CD8+ T cells demonstrated that diabetes progression is dependent on CD8+ T cells, with CD4+ T cells playing a lesser role. The data accumulating from TNF-alpha-NOD mice, described in this review, indicates novel pathways by which inflammatory stimuli can precipitate autoimmunity, and suggests newer approaches in the design of therapeutic treatments that prevent beta-cell destruction in IDDM.

Animals↗