Tumor Necrosis Factor Alpha Antibody Research Articles

Remission of intestinal Behçet's disease treated with anti-tumor necrosis factor α monoclonal antibody (Infliximab)

Behçet's disease (BD) is a chronic relapsing multisystem disease characterized by oral ulceration, genital ulceration and ocular lesions. Gastrointestinal involvement is rare, often difficult to treat and associated with a high mortality rate. We treated a 47-year-old Korean man with BD who had a recurrent intestinal ulcer with tumor necrosis factor α antibody (infliximab); he initially underwent right hemicolectomy due to uncontrolled intestinal bleeding. For patients with intestinal BD who fail to respond to conventional treatment, infliximab may be a safe and effective new therapeutic option.

Adalimumab in the Management of Crohn's Disease (CD) Patients with a Loss of Response to Infliximab

Aims: Chimeric tumour necrosis factor (TNF) alpha antibody, infliximab, is an effective therapy for active CD. Patients may become unresponsive to this therapy over time. Aim: to determine the efficacy of adalimumab, a fully humanised anti-TNF-alpha antibody, in CD patients who lost response to infliximab.

Cytokine-Induced Osteoclastic Bone Resorption in Charcot Arthropathy: An Immunohistochemical Study

Charcot arthropathy is a chronic, progressive destructive process affecting bone architecture and joint alignment in people lacking protective sensation. The etiologic factors leading to progressive bone resorption have not been elucidated. The purpose of this study was to histologically examine surgical specimens with Charcot arthropathy for cell type and immunoreactivity of known cytokine mediators of bone resorption. Tissue samples of 20 specimens with known Charcot arthropathy were stained for Hematoxylin and Eosin (H&E) to quantify cell type. Nine of the specimens were stained with interleukin-1 (IL-1) antibody, nine with tumor necrosis factor (TNF) alpha antibody, and nine with interleukin-6 (IL-6) antibody. Distribution of staining was graded as focal (less than 10% of cells), moderate (10% to 50% of cells), and diffuse (more than 50% of cells) by two independent investigators. Inflammatory cells in tissue sections of rheumatoid synovium served as a positive control. Osteoclasts were seen in excessive numbers lining the resorptive bone lacunae. There was a disproportionate increase in osteoclasts to osteoblasts in the Charcot-reactive bone. In each case, osteoclasts demonstrated immunoreactivity for IL-1, IL-6 and TNF-alpha with a grade of moderate or diffuse reactivity. The findings of excessive osteoclastic activity in the environment of cytokine mediators of bone resorption (IL-1, IL-6, and TNF-alpha) suggest enhanced bone resorption through the stimulation of osteoclastic progenitor cells as well as mature osteoclasts. Alteration in the synthesis, secretion, or activity of these important regulatory molecules through the use of pharmacologic agents may, in turn, alter bone remodeling and loss and lead to accelerated healing without collapse or malalignment.

Role of Tumor Necrosis Factor-α in Sensorineural Hearing Loss after Bacterial Meningitis

Blockade of tumor necrosis factor-alpha with tumor necrosis factor-alpha antibody will reduce the extent of cochlear injury and hearing loss associated with Streptococcus pneumoniae meningitis. Inflammatory mediators play a significant role in the morbidity associated with bacterial meningitis, including hearing loss and labyrinthitis ossificans. Previous studies have shown the attenuation of hearing loss by the nonspecific blockade of such pathways. Fifty Mongolian gerbils were divided into four groups. Auditory brainstem response testing was conducted to measure hearing thresholds. Streptococcus pneumoniae meningitis was induced in Groups 1 and 2. Group 2 was then given a single intraperitoneal injection of tumor necrosis factor-alpha antibody, whereas Group 1 received phosphate-buffered saline. Uninfected animals in Groups 3 and 4 were implanted with osmotic pumps that delivered a continuous 8-day intrathecal flow of either tumor necrosis factor-alpha (Group 4) or phosphate-buffered saline (Group 3). After 6 weeks, auditory brainstem response testing was repeated. The cochleas were harvested and analyzed histomorphometrically. Group 2 animals with Streptococcus pneumoniae meningitis that also received tumor necrosis factor-alpha antibody developed significantly less hearing loss than Group 1 animals with meningitis alone. The decrease in the average threshold at 4, 8, 16, and 32 kHz was 31, 30, 25, and 28 dB sound pressure level, respectively (p < 0.0092 for each). Furthermore, histomorphometric analysis showed significantly less damage to the organ of Corti, spiral ganglion, spiral ligament, and stria vascularis in Group 2. Conversely, tumor necrosis factor-alpha induced meningitis animals (Group 3) showed increased hearing loss compared with phosphate-buffered saline controls (Group 4), with p < 0.0001 at all frequencies. Tumor necrosis factor-alpha plays an important role in cochlear injury after bacterial meningitis. Blockade of tumor necrosis factor-alpha reduces postmeningitic hearing loss and cochlear injury. Induction of meningitis with intrathecal tumor necrosis factor-alpha also resulted in hearing loss and cochlear injury similar to bacterial meningitis.

Infliximab Efficacy in Pediatric Ulcerative Colitis

The effects of infliximab, a tumor necrosis factor-alpha (TNF-alpha) antibody, have been well established in adult patients with inflammatory and fistulizing Crohn's disease. This study evaluates short- and long-term efficacy of infliximab in children with ulcerative colitis. All pediatric patients with ulcerative colitis who received infliximab between July 2001 and November 2003 at the Johns Hopkins Children's Center were identified. Short- and long-term outcomes and adverse reactions were evaluated. Twelve pediatric patients with ulcerative colitis received infliximab for treatment of fulminant colitis (3 patients), acute exacerbation of colitis (3), steroid-dependent colitis (5), and steroid-refractory colitis (1). Nine patients had a complete short-term response, and 3 had partial improvement. The mean per patient dose of corticosteroid after the first infliximab infusion decreased from 45 mg/day at the first infusion to 22.2 mg/day at 4 weeks (P = 0.02) and 7.8 mg/day at 8 weeks (P = 0.008). Eight patients were classified as long-term responders with a median follow-up time of 10.4 months. Of the 4 long-term nonresponders, 3 underwent colectomy, and the fourth has ongoing chronic symptoms. Three of 4 long-term nonresponders were steroid-refractory compared with 1 of 8 long-term responders. Patients receiving 6-mercaptopurine had a better response to infliximab. Infliximab should be considered in the treatment of children with symptoms of acute moderate to severe ulcerative colitis.

Isolated sarcoid granulomatous interstitial nephritis responding to infliximab therapy

Sarcoidosis is a systemic disease with multiorgan involvement. In children, renal impairment of sarcoidosis usually is caused by either hypercalcemia leading to nephrocalcinosis or interstitial nephritis with or without granulomata. We report the case of a 13-year-old boy presenting with severe arterial hypertension and acute renal failure caused by an isolated sarcoid granulomatous interstitial nephritis (GIN). Other known causes of GIN, eg, drug intake or fungal or mycobacterial infection, were excluded, and there was no evidence of extrarenal sarcoid involvement. Renal function improved initially with prednisone treatment. Blood pressure was controlled using ramipril, nifedipine, furosemide, dihydralazine, and metoprolol. Later, the patient showed signs of severe steroid toxicity and progressive renal failure. Monthly treatment with infliximab, a tumor necrosis factor-alpha antibody, was started, resulting in steady improvement in renal function and resolution of renal granulomata. In addition, antihypertensive medication could be reduced, and low-dose prednisone therapy was maintained. To our knowledge, this is the first report of successful treatment with infliximab of a patient with sarcoid GIN.

Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumor necrosis factor alpha antibody infliximab

Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumor necrosis factor alpha antibody infliximab

Cytomegalovirus Retinitis in a Patient Treated with Anti--Tumor Necrosis Factor Alpha Antibody Therapy for Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF- alpha ) antibodies have been used for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis arthritis. Such antibody therapies result in a severe interference with the patient's immune system. Increased rates of upper respiratory tract infection, reactivation of latent tuberculosis, and other systemic infectious diseases have been reported among patients receiving anti-TNF- alpha antibodies. As a note of caution, we describe a 57-year-old woman who received therapy with anti-TNF- alpha antibodies for RA refractory to methotrexate. After almost 2 years of treatment, she developed a severe cytomegalovirus (CMV) retinitis of the right eye. Laboratory assays revealed an immune status with nearly total loss of the cellular immune response and partial reduction of the humoral immune response. Intravenous treatment with ganciclovir, followed by oral administration of valganciclovir, resulted in an ophthalmological remission. Cessation of immunosuppressive therapy led to partial immunological reconstitution in the patient. Six months after discontinuation of immunosuppressive therapy, CMV retinitis of the left eye occurred but was treated successfully with a second course of oral valganciclovir. In the light of this first reported case of a serious CMV infection following therapy with anti-TNF- alpha antibodies, CMV infection should be considered in symptomatic patients.

Effects of superoxide dismutase and polyclonal tumor necrosis factor-alpha antibodies on chloroacetate-induced cellular death and superoxide anion production by J774.A1 macrophages

Dichloroacetate (DCA) and trichloroacetate (TCA) are by-products that are formed during the process of water chlorination and have been previously shown to induce superoxide anion (SA) production and cellular death when added to J774.A1 macrophage cultures. In this study, the effects of superoxide dismutase (SOD) and polyclonal tumor necrosis factor-alpha (TNF-α) antibodies on DCA- and TCA-induced SA production and cellular death have been tested on the J774.A1 macrophage cultures. TCA and DCA were added to different cultures either alone, each at a concentration of 16 mM, or in combination with SOD (2–12 units/ml), or with TNF-α antibodies (10 and 25 units/ml). Cells were incubated for 48 h, after which cellular death/viability, lactate dehydrognase (LDH) leakage by the cells, and SA production by the cells were determined. While TCA and DCA caused significant cellular toxicity, indicated by reduction in cellular viability and increases in LDH leakage and SA production, SOD addition resulted in significant reduction of the effects induced by the compounds. On the other hand, addition of TNF-α antibodies to the DCA- and TCA-treated cultures resulted in significant reduction of DCA- but not TCA-induced cellular death and SA production by the cells. Although these results suggest a significant role for SA in DCA- and TCA-induced cellular death, they may also suggest two different mechanisms for the chloroacetate-induced SA production by the cells.

Brain-derived tumor necrosis factor-alpha and its involvement in noradrenergic neuron functioning involved in the mechanism of action of an antidepressant.

The present study documents a role for brain-derived tumor necrosis factor-alpha (TNF) in the mechanism of action of the antidepressant drug desmethylimipramine (desipramine). To establish this role, field stimulation and superfusion of rat hippocampal slices was employed to investigate the regulation of norepinephrine (NE) release by TNF. Chronic desipramine administration transforms TNF-mediated inhibition of NE release to facilitation, dependent upon alpha2-adrenergic receptor activation. Chronic i.c.v. microinfusion of polyclonal TNF antibody (pTNF-Ab) similarly transforms TNF inhibition of NE release to facilitation. To determine whether this transformation is due to desipramine-induced inhibition of TNF bioactivity in the brain, rats were i.c.v. microinfused with recombinant rat TNF (rrTNF) for 14 days, either alone or with simultaneous i.p. desipramine administration. TNF regulation of NE release in hippocampal slices isolated from these rats was compared with slices isolated from rats chronically administered desipramine alone. Although simultaneous microinfusion of rrTNF with chronic desipramine administration prevents the transformation induced by desipramine, microinfusion of rrTNF enhances TNF inhibition of NE release. These cellular events correspond to changes in immobility, analyzed by the forced swim test (FST). Intracerebroventricular microinfusion of rrTNF increases the duration of immobility of rats in the FST, compared with rats microinfused with aCSF. Desipramine administered chronically decreases immobility duration, which is mimicked by i.c.v. microinfusion of pTNF-Ab and prevented by simultaneous i.c.v. microinfusion of rrTNF. Thus, i.c.v. microinfusion of rrTNF with concomitant desipramine administration opposes decreases in neuron-associated TNF levels, required to transform presynaptic sensitivity to TNF, which is necessary for the drug to be efficacious.

Protective effects of tumor necrosis factor alpha antibody and ulinastatin on liver ischemic reperfusion in rats.

To study the protective effects of tumor necrosis factor alpha (TNF alpha) antibody and ulinastatin on liver ischemic reperfusion in rats. One hundred and twenty male SD rats were randomly divided into four groups: normal control group, ischemic group, TNF alpha antibody group and TNF alpha antibody + ulinastatin group. The animals were killed at 0, 3, 6, 9, 12 h after ischemia for 60 min and followed by reperfusion. Serum alanine aminotransferase (ALT), malondialdehyde (MDA) and liver histopathology were observed. After ischemic reperfusion, the serum ALT and MDA were remarkably increased, and the hepatic congestion was obvious. Treatment of TNF alpha antibody and ulinastatin could significantly decrease serum ALT and MDA levels, and relieve hepatic congestion. Ulinastatin and TNF alpha antibody can suppress the inflammatory reaction induced by hepatic ischemic reperfusion, and have protective effects on rat hepatic ischemic reperfusion injury.

Tumor necrosis factor alpha antibody prevents brain damage of rats with acute necrotizing pancreatitis.

To study the protective effects of tumor necrosis factor alpha (TNFalpha) antibody on pancreatic encephalopathy in rats. One hundred and twenty SD rats were randomly divided into normal control group, acute necrotizing pancreatitis group and TNFalpha antibody treated group. Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct. Serum TNFalpha was detected and animals were killed 12 h after drug administration. Changes in content of brain water, MDA and SOD as well as leucocyte adhesion of brain microvessels were measured. In TNFalpha antibody treated group, serum TNFalpha level was decreased. Content of brain water, MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P<0.05). TNFalpha antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.

Tumor necrosis factor-alpha antibody for induction of remission in Crohn's disease.

Crohn's disease may be refractory to conventional treatments such as corticosteroids, enteral nutrition and immuno-suppressive agents. A number of patients with the disease may also become steroid-dependent leading to increased risk of developing steroid-related adverse effects. Recent studies suggest that TNF-a blocking agents may be effective in inducing remission in Crohn's disease. To conduct a systematic review to evaluate the effectiveness of TNF-a blocking agents in inducing remission in patients with active Crohn's disease. We searched MEDLINE (1966-June 2003), EMBASE (1984-June 2003), the Cochrane Central Register of Controlled Trials from the Cochrane Library (Issue 2, 2003) and the IBD Review Group Specialized Trials Register. We hand-searched the articles cited in each publication obtained. We included only randomised controlled trials in which patients with active Crohn's disease (defined by a validated Crohn's disease activity index) were randomly allocated to receive a TNF-a blocking agent in the treatment arm, or to receive placebo or another treatment in the comparison arm. Data extraction and assessment of the methodological quality of each trial were independently performed by two reviewers. Any disagreement among reviewers was resolved by consensus. Outcome measures reported in the primary studies included clinical remission, clinical response and changes in disease activity index. Ten studies were identified of which 4 met the inclusion criteria. The included studies either differed in the type of TNF-a blocking agent used or in the way outcomes were assessed to such an extent that we considered it inappropriate to combine the data statistically. There is evidence from one randomised controlled trial that suggests that a single intravenous infusion of the monoclonal antibody cA2, infliximab, may be effective for induction of remission in Crohn's disease. There was no difference in response rates among infliximab doses of 5, 10 or 20 mg/kg. The results of two other trials suggested that CDP571, the genetically engineered human TNF monoclonal antibody, may also be effective in reducing disease activity index at 2 weeks after an infusion. We did not find any evidence to support the use of etanercept in Crohn's disease. Evidence from one randomized controlled trial suggests that a single infusion of infliximab may be effective for induction of remission in Crohn's disease. Based on this study, we can recommend a dose of 5 mg/kg. There is also some evidence that CDP571 may be effective in inducing remission in Crohn's disease. We did not find any evidence that supports the use of etanercept in Crohn's disease. The period of follow up for the patients in these studies was probably too short to allow adequate assessment of recently reported serious adverse effects such as tuberculosis and lymphoma.

Galectin 3 and its binding protein in rheumatoid arthritis.

To characterize the expression pattern and role of galectin 3 and galectin 3 binding protein (G3BP) in rheumatoid arthritis (RA), in comparison with galectin 1, and to explore whether soluble galectin 3 and G3BP, investigated in serum, synovial fluid, or cell culture supernatant, are associated with disease. Synovial tissues from patients with RA or osteoarthritis (OA), as well as from healthy controls, were analyzed for galectins 1 and 3 and G3BP by in situ hybridization and immunohistochemistry. Levels of galectin 3 and G3BP in serum and synovial fluid from patients with RA and OA and controls, as well as in cell culture supernatants, were determined by enzyme-linked immunosorbent assay (ELISA). In vitro, the intracellular expression of galectin 3 in RA and OA synovial fibroblasts after modulation with tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and anti-CD40 monoclonal antibodies was measured by flow cytometry. In RA, galectin 3 messenger RNA and protein stained throughout the synovial membrane, whereas G3BP was particularly expressed at sites of bone destruction. In contrast, the expression of galectin 1 was not uniform in different RA specimens, and was never found at sites of invasion. In OA and normal synovial tissues, only a small number of cells were positive for galectins and/or G3BP. Galectin 3 was elevated in RA sera and synovial fluids, whereas G3BP was increased in RA synovial fluids only. In RA, serum galectin 3 correlated with C-reactive protein levels, whereas G3BP was associated with joint destruction and/or synovial cell activation as measured by the levels of cartilage oligomeric matrix protein. In vitro, RA synovial fibroblasts showed an increased release of galectin 3 into culture medium, as measured by ELISA, but decreased secretion of G3BP. In RA synovial fibroblasts with low basal expression of galectin 3, TNFalpha increased its intracellular level in a dose-dependent manner. In contrast, IL-1beta or anti-CD40 monoclonal antibodies showed no effect. Our data indicate that galectin 3 and G3BP are not only involved in inflammation, but also contribute to the activation of synovial fibroblasts. The intracellular accumulation of galectin 3 can be enhanced by TNFalpha. Thus, galectin 3 and G3BP represent novel markers of disease activity in RA.

Down-regulation of the nonspecific and antigen-specific T cell cytokine response in ankylosing spondylitis during treatment with infliximab.

Treatment of active ankylosing spondylitis (AS) with the monoclonal tumor necrosis factor alpha (TNF alpha) antibody infliximab is highly clinically effective. This study was undertaken to investigate the precise mechanism of action of anti-TNF alpha treatment in AS. Cytokine expression of CD4+ and CD8+ T cells was investigated before and 6 and 12 weeks after the start of treatment in 10 patients treated with infliximab, and before and after 6 weeks of treatment and 6 weeks after placebo was switched to infliximab in 10 patients treated initially with placebo. Peripheral blood mononuclear cells (PBMCs) were stimulated for 6 hours either nonspecifically with phorbol myristate acetate (PMA)/ionomycin or antigen specifically with a pool of 46 overlapping 18-mer peptides derived from the G1 domain of aggrecan. Cells were stained for T cell surface markers CD4 and CD8 and for the intracellular cytokines interferon-gamma (IFN gamma), TNF alpha, interleukin-4 (IL-4), and IL-10. Positive cells were quantified by flow cytometry. For monocyte-derived cytokines, PBMCs were stimulated with lipopolysaccharide (LPS) for 18 hours and TNF alpha and IL-10 in the supernatant were measured by enzyme-linked immunosorbent assay. Compared with baseline, infliximab treatment induced a significant decrease at 12 weeks in the number of CD4+ and CD8+ T cells that were positive for IFN gamma and TNF alpha upon PMA/ionomycin stimulation (P = 0.005). A significant reduction had already begun to occur at 6 weeks. No change in the percent IFN gamma or TNF alpha positivity among CD4+ and CD8+ subpopulations was observed after 6 weeks in patients treated with placebo. However, when these patients began infliximab treatment after 6 weeks of receiving placebo, there was a similar significant decrease in IFN gamma and TNF alpha production by CD4+ and CD8+ T cells (P < 0.05). Furthermore, infliximab treatment induced a significant reduction in the number of IFN gamma+ and TNF alpha+ CD8+ T cells (P = 0.005 at week 6 and week 12) after antigen-specific in vitro stimulation with G1-derived peptides. Between-group analysis showed that the change in the expression of IFN gamma and TNF alpha in both CD4+ and CD8+ T cells was significantly different between the infliximab and placebo groups (P = 0.001 for all variables). There was no change in the number of IL-10+ or IL-4+ T cells during treatment. No significant change in the production of TNFalpha and IL-10 upon in vitro stimulation of PBMCs with LPS was detectable during infliximab treatment. Infliximab down-regulates both IFN gamma and TNF alpha secreted by T cells but does not induce a change in cytokines produced by monocytes during 3 months of treatment. This is likely to be a relevant mechanism for the clinical efficacy of this therapy.

Tumour Necrosis Factor Alpha Antibody Affects Gastrin Release in Crohn Disease

Background: Gastrin plays an important role in the regulation of gastric acid secretion in humans. Tumour necrosis factor alpha (TNF-α) stimulates gastrin release from antral G cells in vitro. The aim was to determine whether gastrin release decreases in patients with Crohn disease treated with monoclonal antibody to TNF-α. Methods: Twenty-five consecutive patients with Crohn disease (10 M, 15 F; 18 with fistulas) were treated with a single intravenous infusion of the monoclonal antibody to TNF-α, infliximab, at a dose of 5 mg/kg. Basal and bombesin stimulated gastrin was measured after an overnight fast immediately before and 2 weeks after infliximab. Helicobacter pylori status was determined by serology. Results: Twenty-two patients were H. pylori-negative. Basal plasma gastrin was 21 (16-26) pmol/L before and 19 (15-25) pmol/L after infliximab (NS). Bombesin stimulated gastrin decreased from 49 (40-62) pmol/L before to 36 (33-59) pmol/L (P < 0.005) 2 weeks after infliximab. Conclusion: Gastrin release in response to bombesin decreases in patients with Crohn disease treated with infliximab.

Macrophage inflammatory protein-2 induced by TNF-α plays a pivotal role in concanavalin A-induced liver injury in mice

Background/Aims : Macrophage inflammatory protein-2 (MIP-2), one of the CXC chemokines, is involved in the recruitment of neutrophils in several tissue injuries. In this study, we investigated the role of MIP-2 in concanavalin A (Con A)-induced liver injury in mice. Methods : Liver injury was induced by intravenous injection of Con A (15 mg/kg) and plasma alanine aminotransferase (ALT), MIP-2 levels were determined and histological assessment of the liver was performed. Anti-mouse MIP-2 antibody was intravenously administered 30 min before Con A injection. Results : The plasma ALT level significantly elevated and reached a maximum at 8 h after Con A injection. The plasma MIP-2 level was also elevated and reached a peak value at 2 h after Con A injection. The elevated ALT level by Con A injection was significantly inhibited by the MIP-2 antibody. The elevated plasma MIP-2 level after Con A injection was significantly reduced by the tumor necrosis factor alpha (TNF- α) antibody, and MIP-2 was induced in plasma after recombinant TNF- α injection. Hepatic necrosis and infiltration of neutrophils were observed after Con A injection, and these histological changes were attenuated by the MIP-2 antibody. Conclusions : These findings suggest that Con A induces TNF- α release, and this TNF- α stimulates MIP-2 induction, at least partially contributing to the liver injury mediated through the recruitment of neutrophils.

Interaction between monocytes and vascular smooth muscle cells enhances matrix metalloproteinase-1 production.

Matrix metalloproteinase-1 (MMP-1) plays an important role in atherosclerotic plaque rupture. The purpose of this study was to investigate the expression of MMP-1 by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cells) were cocultured. MMP-1 levels were measured by enzyme-linked immunosorbent assay. Collagenolytic activity was determined by fluorescent labeled-collagen digestion. Immunohistochemistry was performed to determine which types of cells produce MMP-1. Adding THP-1 cells to VSMCs markedly increased the MMP-1 levels and activity of the culture media. MMP-1 levels were maximal when the cellular ratio of THP-1 cells/VSMCs was 1.0. Immunohistochemistry revealed that both types of cells in the coculture produced MMP-1. Separated coculture experiments showed that both direct contact and a soluble factor(s) contributed to MMP-1 production. Neutralizing anti-interleukin (IL)-6 and tumor necrosis factor-alpha antibodies inhibited coculture conditioned medium-induced MMP-1 production by VSMCs and THP-1 cells. Protein kinase C inhibitors, tyrosine kinase inhibitors, and a mitogen-activated protein kinase inhibitor significantly inhibited MMP-1 production by cocultures. Direct cell-to-cell interaction between THP-1 cells and VSMCs enhanced MMP-1 synthesis in both types of cells. Increased local MMP-1 production and activity induced by monocyte-VSMC interaction play an important pathogenic role in atherosclerotic plaque rupture.

Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in crohn's ileocolitis: F.J. Baert, G.R. D'Haens, M. Peelers, et al. Gastroenterology 116:22–28 (January), 1999

Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in crohn's ileocolitis: F.J. Baert, G.R. D'Haens, M. Peelers, et al. Gastroenterology 116:22–28 (January), 1999

Tumor necrosis factor alpha antibody therapy in Crohn's disease

Tumor necrosis factor alpha antibody therapy in Crohn's disease