Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Surfactant protein A (SP-A), the major lung surfactant-associated protein, mediates local defense against pathogens and modulates inflammation in the alveolus. Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine, inhibits SP-A gene expression in lung epithelial cells. Inhibitors of the phosphatidylinositol 3-kinase pathway, i.e., wortmannin, LY-294002, and rapamycin, did not block the inhibitory effects of TNF-alpha on SP-A mRNA levels. An inhibitor of the p44/42 mitogen-activated protein kinase (MAPK) pathway, PD-98059, was also ineffective. PD-169316 and SB-203580, inhibitors of p38 MAPK, blocked the TNF-alpha-mediated inhibition of SP-A mRNA levels. TNF-alpha increased the phosphorylation of p38 MAPK within 15 min. Anisomycin, an activator of p38 MAPK, increased p38 MAPK phosphorylation and decreased SP-A mRNA levels in a dose-dependent manner. Finally, TNF-alpha increased the phosphorylation of ATF-2, a transcription factor that is a p38 MAPK substrate. We conclude that TNF-alpha downregulates SP-A gene expression in lung epithelial cells via the p38 MAPK signal transduction pathway.
Am J Physiol Lung Cell Mol Physiol 2002 Aug
PMID:TNF-alpha inhibits SP-A gene expression in lung epithelial cells via p38 MAPK. 1211 4

Tumor necrosis factor-alpha (TNF-alpha) is believed to play a central role in the pathogenesis of pneumoconiosis. TNF2, a polymorphism in the TNF-a gene promoter, has been associated with an increase in TNF-alpha production and airway inflammation. To investigate the frequency of TNF2 in patients who have coal workers' pneumoconiosis (CWP) and to determine whether it is associated with development of a large opacity in CWP, we investigated the expression ofthe TNF2 allele in 80 patients who had CWP and in 54 healthy controls using restriction fragment length polymorphism (RFLP). Compared to controls (10.2%), the frequency of the TNF2 allele was greater in the CWP patients (20.6%). Furthermore, the TNF2 allele was very common in patients who had a large opacity (28.2%) in comparison with 13.4% in those with simpleCWP. From these data, we suggest that the TNF2 allele is associated with the development of a large opacity in CWP.
Mol Cell Biochem
PMID:Tumor necrosis factor-alpha gene promoter polymorphism in coal workers' pneumoconiosis. 1216 35

Tumor necrosis factor receptor 1 (TNFR1) can trigger distinct signaling pathways leading to either the activation of NF-kappaB transcription factors or apoptosis. NF-kappaB activation results in the expression of antiapoptotic genes that inhibit the apoptosis pathway that is activated in parallel. However, the molecular mechanism of this inhibition remains poorly characterized. We have isolated a Jurkat T-cell mutant that exhibits enhanced sensitivity to TNF-induced apoptosis as a result of a deficiency in I-kappaB kinase gamma (IKKgamma)/NEMO, an essential component of the IKK complex and NF-kappaB pathway. We show here that the zinc finger protein A20 is an NF-kappaB-inducible gene that can protect the IKKgamma-deficient cells from TNF-induced apoptosis by disrupting the recruitment of the death domain signaling molecules TRADD and RIP to the receptor signaling complex. Our study, together with reports on the role of other antiapoptotic proteins such as c-FLIP and c-IAP, suggests that, in order to ensure an effective shutdown of the apoptotic pathway, TNF induces multiple NF-kappaB-dependent genes that inhibit successive steps in the TNFR1 death signaling pathway.
Mol Cell Biol 2002 Sep
PMID:A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. 1216 98

Tranilast [N-(3,4-dimethoxycinnamoyl)anthranilic acid] inhibits vascular inflammation. However, the relevant anti-inflammatory mechanisms are not completely understood. We studied the effects of tranilast on nuclear factor-kappaB (NF-kappaB)-dependent endothelial cell adhesion molecule expression and transcriptional regulation. Cultured human umbilical vein endothelial cells were preincubated with 12.5 to 100 microg/ml tranilast. Tumor necrosis factor-alpha (TNF-alpha)-induced endothelial VCAM-1, ICAM-1, and E-selectin surface expression was inhibited dose dependently. Maximal inhibition achieved with 100 microg/ml tranilast was 38 +/- 6.9, 31.8 +/- 1.5, and 31.9 +/- 1.9%, respectively (mean +/- S.E.M., p < 0.001, n = 5). Secretion of interleukin 6, which is also NF-kappaB-sensitive, was significantly inhibited by tranilast. Endothelial MHC-I expression, which is independent of NF-kappaB, was not inhibited. Although cytokine-induced degradation of NF-kappaB inhibitor proteins (IkappaB-alpha, -beta, and -epsilon), nuclear translocation of NF-kappaB, and binding of NF-kappaB to kappaB cis-acting elements in the adhesion molecule promoters were not affected by tranilast, ICAM-1-kappaB and E-selectin-kappaB reporter gene activity was inhibited by 53% (n = 5, p < 0.01) and 51% (n = 5, p < 0.001), respectively. In contrast, using SP-1 and C/EBP constructs, reporter gene activity was not altered. Expression of the transcriptional coactivator cAMP response element binding protein binding protein (CBP) was inhibited by tranilast, resulting in a loss of interaction between NF-kappaB and CBP. Therefore, in therapeutically relevant concentrations (50 microg/ml), tranilast inhibits NF-kappaB-dependent transcriptional activation by interfering with the NF-kappaB/CBP association. We propose that inhibition of NF-kappaB dependent gene transcription contributes to the anti-inflammatory effects of tranilast.
Mol Pharmacol 2002 Oct
PMID:Tranilast inhibits cytokine-induced nuclear factor kappaB activation in vascular endothelial cells. 1223 32

Tumor necrosis factor (TNF) is a cytokine that mediates many pathophysiologial processes, including angiogenesis. However, the molecular signaling involved in TNF-induced angiogenesis has not been determined. In this study, we examined the role of Etk/Bmx, an endothelial/epithelial tyrosine kinase involved in cell adhesion, migration, and survival in TNF-induced angiogenesis. We show that TNF activates Etk specifically through TNF receptor type 2 (TNFR2) as demonstrated by studies using a specific agonist to TNFR2 and TNFR2-deficient cells. Etk forms a preexisting complex with TNFR2 in a ligand-independent manner, and the association is through multiple domains (pleckstrin homology domain, TEC homology domain, and SH2 domain) of Etk and the C-terminal domain of TNFR2. The C-terminal 16-amino-acid residues of TNFR2 are critical for Etk association and activation, and this Etk-binding and activating motif in TNFR2 is not overlapped with the TNFR-associated factor type 2 (TRAF2)-binding sequence. Thus, TRAF2 is not involved in TNF-induced Etk activation, suggesting a novel mechanism for Etk activation by cytokine receptors. Moreover, a constitutively active form of Etk enhanced, whereas a dominant-negative Etk blocked, TNF-induced endothelial cell migration and tube formation. While most TNF actions have been attributed to TNFR1, our studies demonstrate that Etk is a TNFR2-specific kinase involved in TNF-induced angiogenic events.
Mol Cell Biol 2002 Nov
PMID:Etk/Bmx as a tumor necrosis factor receptor type 2-specific kinase: role in endothelial cell migration and angiogenesis. 1237 Feb 98

IL-1beta inhibits isoproterenol (ISO)-induced relaxation of cultured human airway smooth muscle (HASM) cells. The purpose of this study was to determine whether IL-1beta can also suppress ISO-induced cAMP response element (CRE)-dependent gene expression. ISO (10 microM) caused a marked increase in CRE-binding protein (CREB) phosphorylation, which was attenuated by IL-1beta (2 ng/ml). This effect of IL-1beta was abolished by the cyclooxygenase (COX) inhibitor indomethacin. To examine CRE-driven gene expression, we transiently transfected HASM cells with a construct containing CRE upstream of a luciferase reporter gene. ISO (6 h) caused a sixfold increase in luciferase activity. IL-1beta (24 h) alone also increased luciferase activity, although to a lesser extent (2-fold). However, the ability of ISO to elicit luciferase expression was markedly reduced in cells treated with IL-1beta. Indomethacin, the MEK and p38 inhibitors U-0126 and SB-203580, the protein kinase A inhibitor H-89, and dexamethasone each completely abolished the ability of IL-1beta to induce CRE-driven gene expression but only slightly increased the ability of ISO to induce CRE-driven gene expression in IL-1beta-treated cells. IL-1beta also attenuated dibutyryl cAMP-induced CRE-driven gene expression, but not dibutyryl cAMP-induced CREB phosphorylation. Tumor necrosis factor-alpha (10 ng/ml) also attenuated ISO-induced CRE-driven gene expression, even though it was without effect on ISO-induced cAMP formation or ISO-induced CREB phosphorylation. The results suggest that IL-1beta and tumor necrosis factor-alpha may attenuate the ability of beta-agonists to induce expression of genes with CRE in their regulatory regions at least in part through events downstream of CREB phosphorylation.
Am J Physiol Lung Cell Mol Physiol 2002 Dec
PMID:Effect of IL-1beta on CRE-dependent gene expression in human airway smooth muscle cells. 1238 41

Tumor necrosis factor (TNF) signaling through the TNF receptors involves the recruitment of key signaling factors, leading to the activation of both the transcription factor NF-kappaB and the stress-activated Jun kinase (JNK). In most cells, TNF signaling leads to a rapid and transient increase in JNK activity. However, we show that TNF treatment leads to the sustained activation of JNK in cells that are null for the p65/RelA subunit of NF-kappaB as well as in cells expressing the super-repressor form of IkappaB. In addition, the data indicate that the ability of p65/RelA to regulate gene expression is required to suppress the persistent activation of JNK. Interestingly, this suppression occurs upstream of JNK, within the signal transduction cascade leading to JNK activation, without affecting the stress-activated kinase p38. Since NF-kappaB has previously been shown to be involved in the suppression of TNF-induced apoptosis, we were interested in determining the role of deregulated JNK activity, induced by the loss of NF-kappaB, in controlling the cell death response. Through the use of different approaches for inhibition of JNK, we show that the suppression of JNK activity in cells that lack active NF-kappaB enhances the apoptotic response to TNF. These data suggest that the activity of JNK in cells blocked for NF-kappaB function provides an antiapoptotic signal and explains, at least partly, why a significant number of NF-kappaB null cells remain viable following TNF treatment.
Mol Cell Biol 2002 12
PMID:The p65/RelA subunit of NF-kappaB suppresses the sustained, antiapoptotic activity of Jun kinase induced by tumor necrosis factor. 1241 21

Tumor necrosis factor (TNF) is arguably the most potent inducer of several intracellular signals, including apoptosis, cell differentiation, and gene transcription. It does so through the activation of caspases, specific kinases including mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), transcription factors Activated protein 1 (AP-1), and nuclear factor kappa-B (NF-kappaB). By activating these signals, TNF mediates pro-apoptotic and pro-survival mechanisms in the cell. It has also been suggested that TNF mediates its intracellular signaling by adjusting the redox potential of the cell, specifically through reactive oxygen intermediates (also known as reactive oxygen species). Here we review the evidence linking ROI to TNF-induced signaling and propose that ROI mediate both pro-apoptotic and pro-survival signals. How these antagonistic signals are balanced to maintain homeostasis is still not clear.
Mol Immunol 2002 Dec
PMID:Reactive oxygen intermediates in TNF signaling. 1243 81

Tumor necrosis factor (TNF) signaling is controlled by receptors and intracellular signaling pathways that activate the NF-kappaB transcription factor. The resulting signals elicit immune responses and have important implications for disorders such as autoimmunity or allergic reactions. TNF-receptor-associated factors (TRAFs) bind to the cytoplasmic portion of TNFRs as well as downstream regulators and thus are co-inducers of the signal transduction. TRAF3 binds to diverse receptors and regulators by accomodating a conserved motif that is embedded in completely different structural frameworks. Thus, the protein-protein contact region on TRAF3 represents a binding interface that is structurally and functionally adaptive. In this report, three 'hot spots' at the TRAF3 protein-interaction interface are defined that provide the principal contact regions for different binding partners. The side-chains of residues at these 'hot spots' are flexible and undergo movements on binding the different partners. These side chain rearrangements provide a structural adaptability that promotes interaction with a variety of distinct proteins. It is proposed that similar adaptive 'hot spots' are also present on the binding surfaces of TRAF1, TRAF2 and TRAF5.
J Mol Recognit
PMID:Structurally adaptive hot spots at a protein interaction interface on TRAF3. 1244 5

Cutaneous exposure to sulfur mustard [bis(2-chloroethyl) sulfide; SM] produces a delayed inflammatory skin response and severe tissue injury. Pig skin has organ similarities to human skin that is characterized by the content and types of epidermal lipids, the density of hair follicles and presence of sweat glands, which together afford penetration of topically applied compounds, complex inflammatory responses, and subsequent wound healing. The goal of this study was to identify in vivo proinflammatory biomarkers of the SM porcine skin injury within 72 h after SM challenge, using the weanling pig model. Changes in gene expression of inflammatory mediators were examined at 3, 6, 24, 48, and 72 h, using subtraction library analyses and by quantitation of selected transcripts by reverse transcription-polymerase chain reaction (RT-PCR). Sequence analysis of subtraction libraries identified up-regulation of IL-8 at 24, 48, and 72 h. No other specific proinflammatory gene transcripts were isolated from the libraries. Specific transcript RT-PCR analysis showed increased production of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and matrix metalloproteinase-9 (MMP-9, gelatinase B) mRNA levels in response to SM exposure. Tumor necrosis factor-alpha (TNF-alpha) expression was only slightly increased and no change in the levels of expression was observed for monocyte chemoattractant protein-1 and MMP-2. This study identifies the main proinflammatory mediators involved in SM-induced skin injury in a weanling pig model. The results suggest transcriptional activity in the inflammatory response proteins IL-8, IL-6, IL-1beta, and MMP-9 and modest changes in TNF-alpha that together produce inflammation and contribute to the pathogenesis of SM dermatotoxicity. Therefore, drugs preventing SM-induced inflammation should be prime candidates for medical intervention to lessen collateral inflammation associated with tissue destruction.
J Biochem Mol Toxicol 2002
PMID:Cytokine, chemokine, and matrix metalloproteinase response after sulfur mustard injury to weanling pig skin. 1248 1


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