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At least 1,027 records · Page 57Linked to original sources
PubMed1999

[Involvement of calcineurin-dependent signal pathway in the angiotensin II-induced cardiac myocyte hypertrophy].

The present study was undertaken to observe the role of calcineurin (CaN)-dependent signaling pathway in the angiotensin II (Ang II)-induced cardiac myocyte hypertrophy. In cultured myocardial cells of neonatal rats, Ang II was used to stimulate hypertrophy and CaN-pathway blocked by CsA(an inhibitor of CaN). 3H-leucine incorporation, and activities of CaN, mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) were investigated. The results showed that 3H-leucine incorporation of Ang II-stimulated myocardial cells was 46% higher than control (P < 0.01), which could be inhibited by CsA (0.5-5 micrograms/ml) and PD098059(an inhibitor of MAPK). CaN and PKC activities of Ang II-stimulated myocardial cells were 39% and 280% higher than control (P < 0.001) respectively, while no significant increase in MAPK activities was observed. CsA could reverse the increase of CaN activity, but had no effect on PKC. It is concluded that the CaN-dependent signaling pathway may play an important role in the development of the Ang II-induced cardiac myocyte hypertrophy.

Angiotensin II↗
PubMed2001

Abiotic stress signalling pathways: specificity and cross-talk.

Plants exhibit a variety of responses to abiotic stresses that enable them to tolerate and survive adverse conditions. As we learn more about the signalling pathways leading to these responses, it is becoming clear that they constitute a network that is interconnected at many levels. In this article, we discuss the 'cross-talk' between different signalling pathways and question whether there are any truly specific abiotic stress signalling responses.

Abscisic Acid↗
PubMed1999

Dishevelled proteins lead to two signaling pathways. Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells.

Dishevelled (Dsh/Dvl) proteins are known to mediate Wnt signaling by up-regulating beta-catenin levels and stimulating T cell factor (TCF)/LEF-1-dependent transcription. We have identified a new Dvl-mediated signaling pathway in that mouse Dvl proteins, when expressed in COS-7 cells, stimulate c-Jun-dependent transcription activity and the kinase activity of the c-Jun N-terminal kinase (JNK). The DEP domain of Dvl1 is essential for JNK activation. By contrast, all three conserved domains of Dvl, including DIX, PDZ, and DEP, are required for up-regulation of beta-catenin and for stimulation of LEF-1-mediated transcription in mammalian cells. Thus, Dvl can lead to two different signaling pathways. Furthermore, the small G proteins of Cdc42 or Rac1, which are involved in JNK activation by many stimuli, do not appear to play a major role in Dvl-mediated JNK activation, because the dominant negative mutants of Cdc42 and Rac1 could not inhibit Dvl-induced JNK activation. This suggests that Dvl may activate JNK via novel pathways.

3T3 Cells↗
PubMed1997

Induction of neurite outgrowth in PC12 cells by gamma-lactam-related compounds via Ras-MAP kinase signaling pathway independent mechanism.

Rat pheochromocytoma cells, PC12 cells, undergo differentiation in response to nerve growth factor (NGF). Although the Ras-MAP kinase signaling pathway has been shown to play a central role in the response to NGF, the precise mechanism which induces differentiation remains unclarified. Recently, several gamma-lactam-related microbial products were identified to induce neurite outgrowth in neuroblastoma cells. Therefore, we synthesized a series of gamma-lactam-related compounds and tested for their ability to induce neurite outgrowth in PC12 cells. We found that two compounds, MT-19 and MT-20, induced neurite outgrowth at concentrations as low as 1 microg/ml. MT-19 and MT-20 have an n-hexadecyl group and an n-dodecyl group, respectively, at the position N-1 of the gamma-lactam ring, and the modification of this group leads to partial or complete loss of activity. In addition, the modification of the methyl and hydroxyl group at C-5 leads to complete loss of activity, indicating a strict structure-activity relationship. Interestingly, MT-19 and MT-20 induced neurite outgrowth of PC12 cells which lack normal Ras function. Furthermore, these compounds did not induce MAP kinase activation, suggesting that MT-19 and MT-20 do not require the Ras-MAP kinase signaling pathway which is shown to be necessary and sufficient for NGF-induced neurite outgrowth. Consistent with this, none of the early- or late-response genes tested, which include fos, zif268, Nur77, vgf, and transin, was induced. However, the protein level of three neurofilaments was increased after the incubation with these compounds. Since the level of other cytoskeleton proteins including actin and tubulin remained constant, MT-19 and MT-20 specifically affected neurofilament synthesis and/or turnover. Taken together, these findings indicate that MT-19 and MT-20 induce neurite outgrowth by activating the downstream target of MAP kinase or by a novel mechanism which is distinct from the NGF-activated pathway.

Actins↗
PubMed2003

Fibroblast growth factors regulate prolactin transcription via an atypical Rac-dependent signaling pathway.

Fibroblast growth factors (FGFs) play a critical role in pituitary development and in pituitary tumor formation and progression. We have previously characterized FGF signal transduction and regulation of the tissue-specific rat prolactin (rPRL) promoter in GH4 pituitary cells. FGF induction of rPRL transcription is independent of Ras, but mediated by a protein kinase C-delta (PKCdelta)-dependent activation of MAPK (ERK). Here we demonstrate a functional role for the Rho family monomeric G protein, Rac1, in FGF regulation of PRL gene expression via an atypical signaling pathway. Expression of dominant negative Rac, but not RhoA or Cdc42, selectively inhibited FGF-induced rPRL promoter activity. Moreover, expression of dominant negative Rac also attenuated FGF-2 and FGF-4 stimulation of MAPK (ERK). However, in contrast to other Rac-dependent signaling pathways, FGF activation of rPRL promoter activity was independent of the c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase/Akt cascades. FGFs failed to activate JNK1 or JNK2, and expression of dominant negative JNK or Akt constructs did not block FGF-induced PRL transcription. Consistent with the role of PKCdelta in FGF regulation of PRL gene expression, activation of the rPRL promoter was blocked by an inhibitor of phospholipase Cgamma (PLCgamma) activity. FGF treatment also induced rapid tyrosine phosphorylation of PLCgamma in a Rac-dependent manner. These results suggest that FGF-2 and FGF-4 activate PRL gene expression via a novel Rac1, PLCgamma, PKCdelta, and ERK cascade, independent of phosphoinositol-3-kinase and JNK.

Androstadienes↗
PubMed2002

Effect of redox balance alterations on cellular localization of LAT and downstream T-cell receptor signaling pathways.

The integral membrane protein linker for activation of T cells (LAT) is a central adapter protein in the T-cell receptor (TCR)-mediated signaling pathways. The cellular localization of LAT is extremely sensitive to intracellular redox balance alterations. Reduced intracellular levels of the antioxidant glutathione (GSH), a hallmark of chronic oxidative stress, resulted in the membrane displacement of LAT, abrogated TCR-mediated signaling and consequently hyporesponsiveness of T lymphocytes. The membrane displacement of LAT is accompanied by a considerable difference in the mobility of LAT upon native and nonreducing denaturing polyacrylamide gel electrophoresis analysis, a finding indicative of a conformational change. Targeted mutation of redox-sensitive cysteine residues within LAT created LAT mutants which remain membrane anchored under conditions of chronic oxidative stress. The expression of redox-insensitive LAT mutants allows for restoration of TCR-mediated signal transduction, whereas CD28-mediated signaling pathways remained impaired. These results are indicative that the membrane displacement of LAT as a result of redox balance alterations is a consequence of a conformational change interfering with the insertion of LAT into the plasma membrane. Conclusively, the data suggest a role for LAT as a crucial intermediate in the sensitivity of TCR signaling and hence T lymphocytes toward chronic oxidative stress.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Activation of the TGF-beta/Smad signaling pathway in focal segmental glomerulosclerosis.

BACKGROUND: Although the pathogenetic relevance of transforming growth factor-beta (TGF-beta) to glomerulosclerosis is well established, it is not known whether a signal transduction cascade of TGF-beta is involved in the development of focal segmental glomerulosclerosis (FSGS), nor is it clear how TGF-beta 1 is activated during the course of FSGS formation. METHODS: We examined the expression patterns of TGF-beta 1, thrombospondin-1 (TSP-1), TGF-beta type II receptor (TGF-beta IIR), phosphorylated Smad2/Smad3, and podocyte-specific epitopes [Wilms' tumor protein-1 (WT-1) and glomerular epithelial protein-1 (GLEPP-1)] in 15 renal biopsy specimens with idiopathic FSGS and six renal biopsies with no detectable abnormalities by means of immunohistochemistry. The mRNA expression patterns of TGF-beta 1, TGF-beta IIR, and TSP-1 were further evaluated by in situ hybridization in seven biopsies. RESULTS: In the controls, immunostaining for TGF-beta 1, TSP-1, TGF-beta IIR, and phosphorylated Smad2/Smad3 was almost negligible, but an apparent signal for TGF-beta 1, TSP-1, and TGF-beta IIR mRNAs was observed in the visceral glomerular epithelial cells (GEC). In the cases of FSGS, the expression levels of TGF-beta 1, TSP-1, and TGF-betaIIR proteins and mRNAs and phosphorylated Smad2/Smad3 were significantly increased, particularly in the GEC of the sclerotic segments, wherein WT-1 and GLEPP-1 were not detected. CONCLUSION: These results suggest that damage to podocyes may stimulate TGF-beta 1, TSP-1, and TGF-beta IIR expression in GEC, thereby activating the Smad signaling pathway and, in so doing, leading to overproduction of the extracellular matrix (ECM). Thus, a signal transduction cascade of the TGF-beta/Smad signaling pathway, which is activated in the GEC, appears to be involved in the development of FSGS.

Adolescent↗
PubMed1995

Signaling pathways regulating ornithine decarboxylase activity in the embryonic chicken.

The pathways regulating ornithine decarboxylase (ODC) activity in the chick embryo were studied to determine which kinase-signaling pathways regulate ODC activity levels during development. Insulin-dependent tyrosine kinase, protein kinase C and cAMP-dependent protein kinase were activated by the addition of insulin, tetradecanoylphorbol-12,13-acetate, and forskolin, respectively. All three drugs increased ODC activity and forskolin combined with insulin increased ODC activity above the increase caused by either drug alone. These results suggest that all three signaling pathways regulate ODC activity during development and that common intermediates exist among the pathways downstream of the kinases.

Animals↗
PubMed2004

Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow.

Endothelial cells (ECs) are constantly exposed to shear stress, the action of which triggers signaling pathways and cellular responses. During inflammation, cytokines such as IL-6 increase in plasma. In this study, we examined the effects of steady flow on IL-6-induced endothelial responses. ECs exposed to IL-6 exhibited STAT3 activation via phosphorylation of Tyr705. However, when ECs were subjected to shear stress, shear force-dependent suppression of IL-6-induced STAT3 phosphorylation was observed. IL-6 treatment increased the phosphorylation of JAK2, an upstream activator of STAT3. Consistently, shear stress significantly reduced IL-6-induced JAK2 activation. Pretreatment of ECs with an inhibitor of MEK1 did not alter this suppression by shear stress, indicating that extracellular signal-regulated kinase (ERK1/2) was not involved. However, pretreatment of ECs with an endothelial nitric oxide synthase inhibitor (nitro-l-arginine methyl ester) attenuated this inhibitory effect of shear stress on STAT3 phosphorylation. Shear stress-treated ECs displayed decreased nuclear transmigration of STAT3 and reduced STAT3 binding to DNA. Intriguingly, ECs exposed to IL-6 entered the cell cycle, as evidenced by increasing G(2)/M phase, and shear stress to these ECs significantly reduced IL-6-induced cell cycle progression. STAT3-mediated IL-6-induced cell cycle was confirmed by the inhibition of the cell cycle in ECs infected with adenovirus carrying the inactive mutant of STAT3. Our study clearly shows that shear stress exerts its inhibitory regulation by suppressing the IL-6-induced JAK2/STAT3 signaling pathway and thus inhibits IL-6-induced EC proliferation. This shear force-dependent inhibition of IL-6-induced JAK2/STAT3 activation provides new insights into the vasoprotective effects of steady flow on ECs against cytokine-induced responses.

Animals↗
PubMed1995

Signalling pathways in cardiac failure.

UNLABELLED: 1. Cardiac failure in humans and in animal models is associated with a marked desensitization of the catecholamine signalling pathway. 2. Beta 1- and beta 2- and possibly beta 3-adrenoceptors (beta-AR) are found in the hearts of humans and common laboratory animals such as rats and guinea-pigs. In rats and guinea-pigs chronic stimulation of cardiac beta-AR leads to a rapid loss of beta 2-AR whereas heart failure in humans is associated with a loss of beta 1-AR or beta 1-AR and beta 2-AR. 3. Desensitization is also associated with phosphorylation of beta-AR by beta-AR kinase (beta-ARK) and uncoupling of receptors from the signalling pathway. Beta-ARK but not beta-arrestin activity and mRNA are markedly increased in heart failure. 4. Chronic beta-AR stimulation and heart failure are associated with increases in Gi alpha but little if any change in Gs alpha. 5. The roles of beta gamma subunits of G-proteins, adenylate cyclase subtypes and cAMP dependent protein kinase A in heart failure are unclear at present. ABBREVIATIONS: beta-ARK - beta-adrenoceptor kinase AR - adrenoceptor G-protein - GTP binding protein

Animals↗
PubMed2003

Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells.

The effects of IL-6 on prostate cancer cells are well documented yet remain controversial. Some reports suggested that IL-6 could promote prostate cancer cell growth, while others showed that IL-6 could repress prostate cancer cell growth. Here, we systemically examined various IL-6 signaling pathways in prostate cancer cells and found that IL-6 could go through at least three distinct pathways to modulate the functions of androgen receptor (AR), a key transcriptional factor to control the prostate cancer growth. Our results show that IL-6 can enhance AR transactivation via either the STAT3 or MAPK pathways. In contrast, IL-6 can suppress AR transactivation via the PI3K-Akt pathway. Co-existence of these various signaling pathways may result in either additive or conflicting effects on AR transactivation. Together, our results indicate that the balance of these various pathways may then determine the overall effect of IL-6 on AR transactivation.

DNA-Binding Proteins↗
PubMed2005

Ethylene signaling pathway.

The structural simplicity of the plant hormone ethylene contrasts with its dramatic effects in various developmental processes, as well as in the cellular processes that ethylene initiates in response to a diversity of environmental signals. A single well-conserved signaling cascade mediates this broad spectrum of responses. Ethylene is perceived by a family of two-component histidine kinase receptors that become inactivated upon ethylene binding. In the absence of the hormone, the receptors activate CTR1, a negative regulator of ethylene responses. Sequence similarity between CTR1 and the Raf protein kinases implies involvement of a mitogen-activated protein kinase cascade in this signaling pathway. The protein EIN2 acts downstream of CTR1 and the possible kinase cascade. Although the biochemical function of EIN2 is not understood, its critical role is manifested by the complete ethylene insensitivity of EIN2 loss-of-function mutants. Downstream of EIN2, a family of plant-specific EIN3-like transcription factors mediate ethylene responses. The regulation of EIN3 stability by ethylene is accomplished by F-box-containing proteins that participate in the formation of a SKP1/cullin/F-box complex that targets proteins for degradation by the proteasome. A large number of ethylene-regulated genes have been identified, including the APETALA2 domain-containing transcription factor genes ERF1 and EDF1 to 4, which suggests the participation of a transcriptional cascade in the ethylene response. The differential regulation of some components of this complex nuclear cascade by other signaling pathways provides a possible mechanism for interaction and signal integration. As new points of intersection with other pathways and additional participants in the pathway are identified, the Connections Map will be updated to include this new information.

Arabidopsis↗
PubMed2000

Cross-talk between signal transducer and activator of transcription (Stat5) and thyroid hormone receptor-beta 1 (TRbeta1) signaling pathways.

PRL and T3 are involved in antagonistic regulations during various developmental processes in vertebrate species. We have studied cross-talk between transcription factors activated by these signaling pathways, i.e. signal transducer and activator of transcription 5 (Stat5) and thyroid hormone receptor beta1 (TRbeta1). Liganded TRbeta1 in the presence of its heterodimeric partner, retinoid X receptor gamma (RXRgamma), inhibited the PRL-induced Stat5a- and Stat5b-dependent reporter gene expression by up to 60%. This T3-inhibitory effect studied on Stat5 activity was partly reversed by overexpression of a TRbeta1 dominant negative variant mutated within its nuclear localization signal (TR2A). We next showed that TRbeta1 and TR2A in the presence of RXRgamma increased and decreased, respectively, Stat5 localization into the nucleus regardless of hormonal stimulation. Thus, our data suggest that TRbeta1 can be associated with Stat5 in the cytoplasm and may be involved in Stat5 nuclear translocation. In PRL-treated cells overexpressing TRbeta1/RXRgamma, both Stat5 and TRbeta1 were coimmunoprecipitated, indicating physical association of the two transcription factors. In these cells, addition of T3 with ovine (o)PRL decreased the amounts of total and tyrosine-phosphorylated Stat5 in the cytoplasm compared with oPRL-treated cells. In the nucleus, no clear difference was observed on Stat5 DNA-binding after treatment with PRL and T3 vs. PRL alone in TRbeta1/RXRgamma transfected cells. However, antibodies directed against TRbeta1 lowered Stat5-DNA binding and addition of the deacetylase inhibitor trichostatin A (TSA) relieved T3 inhibition on Stat5 transcriptional activity. Thus, we postulated that the negative cross-talk between TR and Stat5 on target genes could involve histone deacetylase recruitment by liganded TRbeta1.

Cell Line↗
PubMed2026

TMEM33 regulates the proliferation and migration of lung adenocarcinoma by promoting the PI3K/AKT/mTOR signaling pathway.

Lung adenocarcinoma is a common type of lung cancer with high incidence and mortality rates. TMEM33, a tumor-associated protein, has not been fully elucidated in lung adenocarcinoma. To explore the expression of TMEM33 in lung adenocarcinoma, its impact on tumor progression, and its role in the PI3K/AKT/mTOR signaling pathway. Key genes associated with lung adenocarcinoma were screened using the Gene Expression Omnibus (GEO) dataset GSE140797 in combination with a weighted correlation network analysis (WGCNA). Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on these key genes. TMEM33 expression in Lung adenocarcinoma patients was validated using data from the TCGA database. The directly interactive molecules were screened through a bioinformatics method. Cellular assays (Western Blot, CCK8, colony formation, scratch assay, Trans well assay) and a nude mouse model were used to investigate the effects of TMEM33 on cell proliferation, migration, and tumor growth. TMEM33 is highly expressed in lung adenocarcinoma tissues (P&#x2009;<&#x2009;0.05) and associated with poor prognosis. Overexpression of TMEM33 promotes cell proliferation and migration, and activates the PI3K/AKT/mTOR signaling pathway (P&#x2009;<&#x2009;0.01). In the nude mouse model, TMEM33 overexpression increases tumor volume (P&#x2009;<&#x2009;0.001), and PI3K/AKT pathway inhibition suppresses these effects (P&#x2009;<&#x2009;0.05, P&#x2009;<&#x2009;0.01). TMEM33 acts as an oncogene in lung adenocarcinoma by activating the PI3K/AKT/mTOR pathway, providing new therapeutic targets.

Cell migration↗
PubMed1996

Calcium entry and mobilization signaling pathways in ANG II-induced renal vasoconstriction in vivo.

The purpose of this study was to determine the relative importance of calcium signaling pathways in angiotensin II (ANG II)-induced renal vasoconstriction in vivo. Nifedipine was used to antagonize dihydropyridine-sensitive voltage-dependent calcium channels; BAY K 8644 was employed to activate these calcium channels. Intracellular calcium mobilization was evaluated using TMB-8 or heparin to inhibit calcium release from sarcoplasmic reticulum. Renal blood flow was measured by electromagnetic flowmetry in anesthetized euvolemic Wistar-Kyoto rats. The animals were pretreated with indomethacin to avoid interactions with prostaglandins. ANG II (2 ng) or BAY K 8644 (1 microgram) was injected into the renal artery to produce a transient 30-50% decrease in renal blood flow without affecting arterial pressure. Coadministration of nifedipine with BAY K 8644 produced dose-dependent inhibition of the maximum renal vasoconstriction elicited by BAY K 8644. The calcium-channel antagonist had similar effects on ANG II-induced renal vasoconstriction. Nifedipine exerted maximum inhibition by blocking 50% of the peak ANG II response. To evaluate intracellular calcium mobilization, TMB-8 or heparin was coadministered with ANG II. Each agent produced dose-dependent inhibition of up to 50% of the maximum renal vasoconstriction produced by ANG II. The inhibitory effects of nifedipine and TMB-8 were additive; neither agent had an effect when ANG II AT1 receptors were antagonized with losartan. These observations indicate that one-half of the ANG II-induced constriction of renal resistance vessels is mediated by voltage-dependent L-type calcium channels responsive to the dihydropyridine nifedipine. The remaining 50% of the renal vasoconstriction elicited by ANG II is mediated by inositol 1,4,5-trisphosphate-mediated calcium mobilization from intracellular sources. The additive nature of the inhibitory effects indicates distinct mechanisms involving calcium mobilization and calcium entry signaling pathways that are of equal importance in ANG II activation of AT1 receptors to trigger constriction of renal resistance vessels under basal conditions.

Angiotensin II↗
PubMed2001

Alterations of the transforming growth factor-beta signaling pathway in hepatocellular carcinomas induced endogenously and exogenously in rats.

To elucidate involvement of the transforming growth factor-beta (TGF-beta) signaling pathway in endogenous and exogenous liver carcinogenesis, we investigated mutations of TGF-beta receptor type II (TGF-betaRII), Smad2 and Smad4 genes, and expression of TGF-betaRII in hepatocellular carcinomas (HCCs) induced by a choline-deficient L-amino acid-defined (CDAA) diet and by N-nitrosodiethylamine (DEN). Male Fischer 344 rats received a CDAA diet continuously and HCCs were sampled after 75 weeks. Administration of DEN was followed by partial hepatectomy (PH), with colchicine to induce cell cycle disturbance and a selection pressure regimen, HCCs being obtained after 42 weeks. Total RNAs were extracted from individual HCCs and mutations in TGF-betaRII, Smad2 and Smad4 were investigated by reverse transcription (RT)-polymerase chain reaction (PCR)-restriction-single-strand conformation polymorphism (SSCP) analysis followed by sequencing analysis. Mutations of Smad2 were detected in 2 out of 12 HCCs (16.7%) induced by the CDAA diet, a GGT-to-GGC transition (Gly to Gly) at codon 30 and a TCT-to-GCT (Ser to Ala) transversion at codon 118, without any TGF-betaRII or Smad4 alterations. No mutations of TGF-betaRII, Smad2 and Smad4 were encountered in eleven HCCs induced by the exogenous carcinogen. Semi-quantitative RT-PCR revealed reduced expression of TGF-betaRII in 2 HCCs (16.7%) without Smad2 mutations out of 12 HCCs induced by the CDAA diet and none of 11 induced by DEN. These results suggest that the TGF-beta signaling pathway may be disturbed in endogenous liver carcinogenesis in rats.

Alkylating Agents↗
PubMed1996

Extracellular simian virus 40 induces an ERK/MAP kinase-independent signalling pathway that activates primary response genes and promotes virus entry.

Simian virus 40 (SV40) binding to growth-arrested cells activated an intracellular signalling pathway that induced the up-regulation of the primary response genes c-myc, c-jun and c-sis within 30 min and of JE within 90 min. The up-regulation of the primary response genes occurred in the presence of cycloheximide and when UV-inactivated SV40 was adsorbed to cells. SV40 binding did not activate Raf or mitogen-activated protein kinase (MAP/ERK1), or mobilize intracellular Ca2+. The SV40-induced up-regulation of c-myc and c-jun was blocked by the tyrosine kinase inhibitor, genistein, and by the protein kinase C (PKC) inhibitor, calphostin C, but not by expression of the MAP kinase-specific phosphatase, MKP-1. These results suggest that the SV40-induced signalling pathway includes the activities of a tyrosine kinase and a Ca(2+)-independent isoform of PKC, but not of Raf or MAP kinase. Finally, SV40 infectious entry into cells was specifically and reversibly blocked by genistein.

Animals↗
PubMed2005

Biomechanical stress induces IL-6 expression in smooth muscle cells via Ras/Rac1-p38 MAPK-NF-kappaB signaling pathways.

IL-6, a proinflammatory cytokine, has been implicated in the development of vascular diseases. We previously demonstrated that mechanical stress can initiate signaling pathways leading to smooth muscle cell (SMC) proliferation and apoptosis, but little is known concerning cyclic stress-induced inflammatory response. To explore the role of stretch in the upregulation of cytokine expression in SMCs we performed RNase protection assay for a panel of cytokines and found that mechanical stress resulted in a time-dependent induction of IL-6 mRNA but not other cytokines, e.g., IL-1alpha, IL-1beta, IL-6, IL-10, IL-12p35, IL-12p40, IL-18, IFN-gamma, and macrophage migration inhibitory factor (MIF). This induction also correlated with elevated IL-6 protein levels in the supernatant. Pretreatment of the cells with NF-kappaB inhibitors inhibited NF-kappaB activity and resulted in marked inhibition (50%) of IL-6 protein. Moreover, SMC lines stably expressing dominant-negative Ras (RasN17) or Rac (RacN17) exhibited a remarkable decrease in p38 MAPK activity and IL-6 mRNA induction by mechanical stress. Furthermore, a significant inhibition of 30 and 40% in IL-6 protein was observed in SMCs pretreated with inhibitors of p38 MAPK and ERK1/2, respectively, but not JNK. Interestingly, SMCs isolated from PKC-delta-deficient mice exhibited higher levels of IL-6 compared with wild-type cells. Finally, high levels of IL-6 expression were observed in atherosclerotic lesions of vein bypass grafts, which are related to altered biomechanical stress. Our findings demonstrate that biomechanical stress-induced IL-6 expression occurs via a mechanism that involves Ras/Rac/p38 MAPK/NF-kappaB/NF-IL6 signaling pathways, which is downregulated by PKC-delta, and suggest that modulation of this event contributes to the pathogenesis of atherosclerosis.

Animals↗