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At least 775 records · Page 43Linked to original sources
PubMed2005

Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease.

Vitamin D-deficient IL-10 knockout (KO) mice develop accelerated inflammatory bowel disease (IBD). Removing dietary calcium from the diets of vitamin D-deficient IL-10 KO mice increased the severity of IBD. The mice fed either calcium or active vitamin D (1 alpha,25-dihydroxyvitamin D3, 1,25D3), developed an intermediate form of IBD, while the mice fed both calcium and 1,25D3 had the mildest form of IBD. TNF-alpha secretion from Con A-stimulated splenocytes was reduced by dietary calcium or 1,25D3 treatment. The IL-10 KO mice that received both high calcium diets and 1,25D3 treatments had the lowest TNF-alpha production. In the colons, a TNF-alpha-inducing transcription factor, LPS-induced TNF-alpha factor (LITAF), was inhibited by 1,25D3, but not by calcium. The inhibition of several TNF-alpha-related genes was associated with the decreased colitis in 1,25D3-treated IL-10 KO mice. Furthermore, fulminating IBD in vitamin D receptor/IL-10 double-KO mice corresponded with the increased expression of TNF-alpha and LITAF in the colon. Our results suggest that dietary calcium has independent effects on IBD severity and that 1,25D3 and high calcium together result in the maximal suppression of experimental IBD. The data support a model where dietary calcium and 1,25D3 treatment directly and indirectly inhibit the TNF-alpha pathway and suppress IBD.

Animals↗
PubMedDate not supplied

Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo.

The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (Abeta)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human Abeta1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress Abeta-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.

Alzheimer Disease↗
PubMed2006

Opposite effects of vascular irradiation on inflammatory response and apoptosis induction in the vessel wall layers via the peroxynitrite-poly(ADP-ribose) polymerase pathway.

PURPOSE: We investigated in a surgical rat model of vascular injury the potential role of the peroxynitrite - poly(ADPribose) polymerase (PARP) pathway in inflammatory response and apoptosis induction after vascular gamma irradiation. METHODS: Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n = 10) and were irradiated with 15 Gray (n = 13) or 20 Gray (n = 10) postoperatively and compared with sham-operated rats (n = 10). Additional animals were solely irradiated with 15 Gy (n = 10) and with 20 Gy (n = 10) to distinguish between primary effects of vascular injury and secondary effects due to irradiation. RESULTS: After 21 days, neointima formation was significantly suppressed after irradiation (control: 0.07 mm(2) +/- 0.04 mm(2), 15 Gy: 0.003 mm(2) +/- 0.004 mm(2), 20 Gy: 0.001 mm(2) +/- 0.0006 mm(2), P< 0.0001). However, a significant inflammation of the vessel wall with focal wall necrosis was detected (control: 0.2 +/- 0.15, 15 Gy: 0.82 +/- 1.2, 20 Gy: 1.25 +/- 0.86, P= 0.003). Immunohistochemistry showed significant staining for nitrotyrosine, poly(ADP-ribose) and nuclear translocation of apoptosis-inducing factor in the neointima of the control group. In the irradiated groups these stainings were significantly higher in the media and adventitia compared to the non-irradiated groups. CONCLUSION: Activation of the peroxynitrite-PARP pathway was demonstrated during neointima proliferation in a rat model of surgical vascular injury. Vascular irradiation suppressed neointima formation, but induced significant activation of the peroxynitrite - PARP pathway in the outer vessel wall layers concomitant to inflammation and focal wall necrosis. This may contribute to adverse effects of vascular irradiation such as fibrosis and constrictive remodeling.

Animals↗
PubMed2006

Tumour necrosis factor alpha blockade induces an anti-inflammatory growth hormone signalling pathway in experimental colitis.

BACKGROUND: Neutralisation of tumour necrosis factor alpha (TNFalpha) restores systemic growth hormone function in patients with Crohn's disease, and induces mucosal healing. Anabolic effects of growth hormone depend on activation of the STAT5 transcription factor. Although it has recently been reported that both administration of growth hormone and neutralisation of TNFalpha reduce mucosal inflammation in experimental colitis, whether this involved activation of STAT5 in the gut is not known. AIM: To determine whether TNFalpha blockade in colitis up regulates a growth hormone:STAT5 signalling pathway in the colon. METHODS: Interleukin 10-deficient mice and wild-type controls received growth hormone or anti-TNFalpha antibody, and T84 human colon carcinoma cells were treated with TNFalpha or growth hormone. Activation and expression of STAT5b, peroxisome proliferator-activated receptor gamma (PPARgamma), NFkappaB/IkappaB and growth hormone receptor were determined. RESULTS: Growth hormone activated STAT5b and up regulated expression of PPARgamma in normal mouse colon; inflamed colon was partially resistant to this. Chronic administration of growth hormone, nevertheless, significantly reduced activation of colonic NFkappaB (p = 0.028). Neutralisation of TNFalpha rapidly increased abundance of growth hormone receptor, activation of STAT5 and abundance of PPARgamma in the colon, but reduced activation of NFkappaB in colitis. Growth hormone activated STAT5, and directly reduced TNFalpha activation of NFkappaB, in T84 cells. CONCLUSIONS: Reduced activation of colonic STAT5 and expression of PPARgamma may contribute to persistent mucosal inflammation in colitis. Up regulation of STAT5 and PPARgamma, either through neutralisation of TNFalpha or chronic administration of growth hormone, may exert an anti-inflammatory effect in inflammatory bowel disease.

Animals↗
PubMed2006

Alpha-lipoic acid modulates ovarian surface epithelial cell growth.

OBJECTIVE: The intracellular redox state plays an important role in controlling inflammation. Clinical and laboratory data suggest that inflammation can lead to tumor progression. We hypothesized that restoring intracellular redox control would inhibit inflammation and subsequently tumor progression. Our studies were designed to investigate the effect of alpha-lipoic acid (ALA), a naturally occurring antioxidant, on a key inflammatory signaling pathway and cell proliferation in normal and tumorigenic ovarian surface epithelial cells. METHODS: Normal and tumorigenic ovarian surface epithelial cells were isolated as described by Roby and coworkers [Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawpik O, Persons DL, Smith PG, Terranova PF, Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogen 2000;21 (4):585. [1]]. The effect of ALA on cellular function was measured in cell proliferation and apoptosis assays. p27(kip1) protein levels were measured by Western analysis. Activation of NF-kappaB dependent transcription was assessed in cell cultures transiently transfected with NF-kappaB controlled reporter constructs. RESULTS: Our results reveal that ALA selectively inhibits the growth of tumorigenic as compared to non-tumorigenic ovarian surface epithelial cells. The growth inhibitory effect of ALA is not due to induction of apoptosis but instead is associated with an increase in the half-life of the cyclin-dependent kinase inhibitor, p27(kip1). In parallel to the growth inhibitory effect, ALA also affects a key inflammatory signaling pathway by inhibiting TNFalpha-induced NF-kappaB signaling activity. CONCLUSIONS: Our studies are the first to show that ALA treatment has a growth inhibitory effect on malignant surface epithelial cells of ovarian origin. We have also confirmed the reproducibility of the immunocompetent mouse ovarian cancer model originally described by Roby and coworkers [Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawpik O, Persons DL, Smith PG, Terranova PF, Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogen 2000;21 (4):585].

Animals↗
PubMed1999

CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway. A target of interleukin (il)-4 and il-10 anti-inflammatory action.

Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD154) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis induced through serum deprivation. Both of these consequences of CD40 stimulation have been shown to be dependent on the induction of protein tyrosine kinase activity. CD40-mediated activation of protein tyrosine kinase activity and subsequent inflammatory cytokine production are abrogated by treatment of monocytes with the T helper type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10). In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinases, whereas phosphorylation of mitogen-activated protein kinases family members p38 and c-Jun N-terminal kinase was not observed in response to this stimuli over the time course examined. PD98059, an inhibitor of the upstream activator of ERK1/2, the MAP/ERK kinase MEK1/2, suppressed IL-1beta and tumor necrosis factor-alpha production in a dose-dependent fashion. Pretreatment of monocytes with IL-4 and IL-10 inhibited CD40-mediated activation of ERK1/2 kinase activity when used individually, and are enhanced in effectiveness when used in combination. Together, the data demonstrate that CD40-mediated induction of IL-1beta and tumor necrosis factor-alpha synthesis is dependent on a MEK/ERK pathway which is obstructed by signals generated through the action of IL-4 and IL-10.

CD40 Antigens↗
PubMed2001

Macrophage control of inflammation: negative pathways of regulation of inflammatory cytokines.

The recruitment of leukocytes from the blood compartment constitutes a multistep process which involves primary and secondary inflammatory cytokines, as well as adhesion molecules expressed on leukocytes and endothelial cells. The properties of the interleukin (IL)-1 system and of chemokines, as well as their interplay, are analysed. These mediators offer new paradigms to understand diverse pathologies, and provide tools and targets for the development of novel therapeutic strategies.

Animals↗
PubMed1996

VCAM-1/alpha 4-integrin adhesion pathway: therapeutic target for allergic inflammatory disorders.

Lymphocyte recirculation and leukocyte extravasation involve a multistep process that is central to immune surveillance and the rapid response of white blood cells to sites of injury or infection. Interaction of vascular adhesion molecules (VCAM-1, ICAM-1, and selectins) with ligands on the leukocyte surface (integrins, carbohydrates, and mucin-like molecules) regulate diapedesis. The nature of an inflammatory stimulus ultimately determines the pattern of endothelial adhesion molecule expression and the avidity state of their counterreceptors, thus dictating to a large extent whether a subclass of leukocytes will play a dominant role in the immune response. Immunoglobulin superfamily member VCAM-1 recognizes alpha 4 beta 1 integrin, expressed on all leukocytes except neutrophils. Blockade or inhibition of VCAM-1/alpha 4 beta 1 interaction is expected to have therapeutic potential in treating various inflammatory disorders and autoimmune diseases since this adhesion pathway has a major influence on eosinophil, lymphocyte, and monocyte trafficking. This review summarizes some of the strategies that are currently used to selectively inhibit the VCAM-1/alpha 4 integrin pathway, including soluble VCAM-Ig fusion protein, peptide antagonists, antisense oligonucleotides, natural products, and neutralizing antibodies to VCAM-1 or alpha 4 integrin.

Animals↗
PubMed2003

Targeting apoptotic signalling pathway and pro-inflammatory cytokine expression as therapeutic intervention in TPE induced lung damage.

Tropical pulmonary eosinophilia (TPE) is an occult manifestation of filariasis, brought about by helminth parasites Wuchereria bancrofti and Brugia malayi. Treatment of patients suffering from TPE involves the administration of diethyl carbamazine and Ivermectin. Although the drugs are able to block acute inflammation, they are not able to alleviate chronic basal inflammation. We have attempted to examine the disease by targeting two important components; namely filarial parasitic sheath proteins (FPP) induced apoptosis and pro-inflammatory cytokine response in human laryngeal carcinoma cells of epithelial origin (HEp-2) cells an epithelial cell line. Earlier studies by us have shown that FPP exposure induced apoptosis in these cells. In this study with hydrocortisone, calpain inhibitor (ALLN) and phorbol myristate acetate (PMA) treatments we demonstrate that apoptosis is inhibited as shown by [3H] thymidine incorporation studies, propidium iodide staining and Annexin V staining. Hydrocortisone at a dose, which inhibits cell death also down regulated, the expression of pro-inflammatory cytokines IL-6 and IL-8. These findings give us insights into the multifaceted approach one may adopt to target critical signalling molecules using appropriate inhibitors, which could eventually be used to reduce lung damage in TPE.

Cell Line↗
PubMed2002

Role of isoprenylcysteine carboxyl methyltransferase in tumor necrosis factor-alpha stimulation of expression of vascular cell adhesion molecule-1 in endothelial cells.

We have previously shown that cytokine stimulation of the expression of vascular cell adhesion molecule-1 (VCAM-1), but not that of intercellular adhesion molecule-1 (ICAM-1), is redox sensitive in endothelial cells. Here, we investigated the role of isoprenylcysteine carboxyl methyltransferase (ICMTase), which methylates isoprenylated CAAX (where C indicates cysteine; A, aliphatic amino acids; and X, almost any other amino acid) proteins, including Rac1, a component of superoxide-generating NAD(P)H oxidase, in the expression of VCAM-1. Pretreatment of endothelial cells with N-acetyl-S-farnesyl-L-cysteine (AFC) or N-acetyl-S-geranylgeranyl-L-cysteine (AGGC), specific inhibitors of ICMTase, inhibited the tumor necrosis factor-alpha (TNF-alpha) stimulation of mRNA expression of VCAM-1 but not that of ICAM-1. Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells. TNF-alpha stimulation of the cells significantly increased the methylation of AFC and Rac1 in endothelial cells. That ICMTase was a component of the redox-sensitive signaling pathway was also suggested by the AFC inhibition of the generation of reactive oxygen species by TNF-alpha. Interestingly, the dominant-negative isoform of Rac1 was not selective but inhibited the TNF-alpha stimulation of the mRNA expression of VCAM-1 and ICAM-1. Thus, ICMTase is a critical component of the redox-sensitive VCAM-1-selective signaling pathway, and it appears to activate a discrete inflammatory signaling pathway, at least in part, through the methylation of Rac1.

Acetylcysteine↗
PubMed1994

Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice.

In a previous survey of inbred mouse strains on an atherogenic diet, we observed that the susceptibility to aortic atherosclerotic lesion formation was associated with the accumulation of lipid peroxidation products, induction of inflammatory genes, and the activation of NF-kB-like transcription factors (Liao, F., A. Andalibi, F. C. deBeer, A. M. Fogelman, and A.J. Lusis. 1993. J. Clin. Invest. 91:2572-2579). We hypothesized that the inflammation-related processes were stimulated by oxidized lipids, since injection of minimally oxidized LDL (MM-LDL) activated the same set of genes. We now report that the induction of inflammatory genes and activation of NF-kB-like transcription factors cosegregate with aortic atherosclerotic lesion formation in BXH recombinant inbred strains derived from parental C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. In addition, the accumulation of hepatic conjugated dienes exhibited a significant correlation with inflammatory gene activation. These results provide strong evidence for the role of inflammatory mediators inducible by oxidative stress in atherogenesis. They also suggest that a major gene contributing to aortic lesion development in this mouse model, designated Ath-1, may control either the accumulation of lipid peroxides in tissues or the cellular responses to such lipid peroxides.

Animals↗
PubMed1994

Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes.

15-Lipoxygenase (15-LO) catalyzes hydroperoxidation of fatty acids, a reaction of potential relevance to inflammation, membrane remodeling, and atherosclerosis. In human leukocytes, 15-lipoxygenation of arachidonic acid produces 15-(S)-hydroxyeicosatetraenoic acid and lipoxin A4, which suppress white cell chemotaxis, adherence, and activation, and antagonize proinflammatory leukotrienes. Interleukin (IL)-13, produced by T-helper subset 2 (TH-2) lymphocytes, specifically and potently induced 15-LO gene expression and enzyme activity in human monocytes. Among other TH-2 lymphokines, this induction of 15-LO is shared by IL-4 but not by IL-10. Interferon-gamma, a product of TH-1 lymphocytes, blocked IL-13-mediated induction of 15-LO. The induction of the anti-inflammatory 15-LO pathway by IL-13 reveals a new facet of IL-13 biology that supports its role as a cytokine with potential to down-regulate inflammatory pathways. The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis.

Arachidonate 15-Lipoxygenase↗
PubMed2005

Pro- and anti-inflammatory cytokines regulate the ERK pathway: implication of the timing for the activation of microglial cells.

Pro-inflammatory molecules induce glial activation and the release of potentially detrimental factors capable of generating oxidative damage, such as nitric oxide (NO) and superoxide anion (O2.-). Activated glial cells (astrocytes and microglia) are associated to the inflammatory process in neurodegenerative diseases. A strong inflammatory response could escape endogenous control becoming toxic to neurons and contributing to the course of the disease. We evaluated in a hippocampal cells-microglia co-culture model, if the pro-inflammatory condition induced by lipopolysaccharide + interferon-gamma (LPS+IFN-gamma) promoted damage directly or if damage was secondary to glial activation. In addition, we explored the effect of the anti-inflammatory cytokine transforming growth factor-beta1 (TGF-beta1), and pro-inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on the regulation of the inflammatory response of microglia. We found that LPS+IFN-gamma-induced damage on hippocampal cultures was dependent on the presence of microglial cells. In hippocampal cultures exposed to LPS+IFN-gamma, TGF-beta1 was induced whereas in microglial cell cultures LPS+IFN-gamma induced the secretion of IL-1beta. TGF-beta1 and IL-1beta but not TNF-alpha decreased the NO production by 70-90%. PD98059, an inhibitor of MAP kinase (MEK), reduced the IFN-gamma-induced NO production by 40%. TGF-beta and IL-1beta reduced the IFN-gamma induced phosphorylation of ERK1,2 by 60% and 40%, respectively. However, the effect of IL-1beta was observed at 30 min and that of TGF-beta1 only after 24 h of exposure. We propose that acting with different timing, TGF-beta1 and IL-1beta can modulate the extracellular signal-regulated kinase ERK1,2, as a common element for different transduction pathways, regulating the amplitude and duration of glial activation in response to LPS+IFN-gamma. Cross-talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases.

Analysis of Variance↗
PubMed2006

Modulation of sensory neuron mechanotransduction by PKC- and nerve growth factor-dependent pathways.

Many sensations of pain are evoked by mechanical stimuli, and in inflammatory conditions, sensitivity to such stimuli is commonly increased. Here we used cultured sensory neurons as a model of the peripheral terminal to investigate the effects of inflammatory signaling pathways on mechanosensitive ion channels. Activation of two of these pathways enhanced transduction in a major population of nociceptors. The proinflammatory neurotrophin nerve growth factor caused an up-regulation of mechanically activated currents via a transcriptional mechanism. Activators of PKC, given in vitro and in vivo, also caused an increase in mechanically activated membrane current and behavioral sensitization to mechanical stimulation, respectively. The effect of activating PKC was inhibited by tetanus toxin, suggesting that insertion of new channels into the cell membrane is involved in sensitization. These results reveal previously undescribed mechanisms by which PKC and nerve growth factor synergistically enhance the response of nociceptors to mechanical stimuli, suggesting possible targets for pain treatment.

Animals↗
PubMed2005

Autonomic neural regulation of immunity.

The 'cytokine theory of disease' states that an overproduction of cytokines can cause the clinical manifestations of disease. Much effort has been expended to determine how cytokines are regulated in normal health. Transcriptional, translational and other molecular control mechanisms protect the host from excessive cytokine production. A recent discovery revealed an unexpected pathway that inhibits macrophage cytokine production. The inflammatory reflex is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signalling. Termed the 'cholinergic anti-inflammatory pathway', efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticuloendothelial system. ACh can interact specifically with macrophage alpha7 subunits of nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release. This 'hard-wired' connection between the nervous and immune systems can be harnessed therapeutically in animal models of inflammatory disease, via direct electrical stimulation of the vagus nerve, or through the use of cholinergic agonists that specifically activate the macrophage alpha7 subunit of the ACh receptor. Autonomic dysfunction has been associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis; whether this dysfunction results from the inflammatory component of these diseases, or is actually an underlying cause, is now less clear. The description of the cholinergic anti-inflammatory now brings to the fore several new therapeutic strategies for inflammatory disease, and suggests that many of these diseases may actually be diseases of autonomic dysfunction.

Autonomic Nervous System↗
PubMed2004

Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production.

In Alzheimer's disease (AD), chronically activated glia contribute to neuronal dysfunction through production of neuroinflammatory molecules like interleukin (IL)-1beta. As a first step to address the signaling pathways important for pro-inflammatory cytokine induction, and whether different activators use distinct pathways, we tested the involvement of mitogen-activated protein kinase (MAPK) pathways in microglial IL-1beta production. Microglial cultures stimulated with lipopolysaccharide, S100B, or beta-amyloid showed rapid activation of three different MAPKs (p38, ERK1/2, and JNK) and a later increase in IL-1beta levels, consistent with a possible mechanistic relationship between MAPK and IL-1beta. To more directly test this possibility, we stimulated microglia in the presence of selective MAPK inhibitors, and found that inhibition of each of the three MAPK pathways inhibited IL-1beta production in a concentration-dependent manner. In addition, the relative importance of each MAPK to IL-1beta production depended on the activating stimulus. These data demonstrate that MAPK pathways are important for microglial IL-1beta production, and suggest that different glial activators use distinct sets of signaling pathways to induce the same disease-relevant end-point in microglia.

Animals↗