scholarly journals Cyclic AMP Inhibits p38 Activation via CREB-Induced Dynein Light Chain

2006 ◽  
Vol 26 (4) ◽  
pp. 1223-1234 ◽  
Author(s):  
Jiyan Zhang ◽  
Truc N. Bui ◽  
Jialing Xiang ◽  
Anning Lin
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Light Chain ◽  
Intracellular Signaling ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Dynein Light Chain ◽  
Necrosis Factor Alpha ◽  
Tnf Α

ABSTRACT The mitogen-activated protein kinase p38 plays a critical role in inflammation, cell cycle progression, differentiation, and apoptosis. The activity of p38 is stimulated by a variety of extracellular stimuli, such as the proinflammatory cytokine tumor necrosis factor alpha (TNF-α), and subjected to regulation by other intracellular signaling pathways, including the cyclic AMP (cAMP) pathway. Yet the underlying mechanism by which cAMP inhibits p38 activation is unknown. Here we show that the induction of dynein light chain (DLC) by cAMP response element-binding protein (CREB) is required for cAMP-mediated inhibition of p38 activation. cAMP inhibits p38 activation via the protein kinase A-CREB pathway. The inhibition is mediated by the CREB target gene Dlc, whose protein product, DLC, interferes with the formation of the MKK3/6-p38 complex, thereby suppressing p38 phosphorylation activation by MKK3/6. The inhibition of p38 activation by cAMP leads to suppression of NF-κB activity and promotion of apoptosis in response to TNF-α. Thus, our results identify DLC as a novel inhibitor of the p38 pathway and provide a molecular mechanism by which cAMP suppresses p38 activation and promotes apoptosis.

scholarly journals Coordinate Regulation of IκB Kinases by Mitogen-Activated Protein Kinase Kinase Kinase 1 and NF-κB-Inducing Kinase

1998 ◽  
Vol 18 (12) ◽  
pp. 7336-7343 ◽  
Author(s):  
Shino Nemoto ◽  
Joseph A. DiDonato ◽  
Anning Lin
Keyword(s):  
Protein Kinase ◽  
Interleukin 1 ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Dominant Negative Mutant ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ikk Complex ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

ABSTRACT IκB kinases (IKKα and IKKβ) are key components of the IKK complex that mediates activation of the transcription factor NF-κB in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-κB-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-α) and interleukin-1 and can potentiate the stimulatory effect of TNF-α on IKK and NF-κB activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-α. MEKK1 interacts with and stimulates the activities of both IKKα and IKKβ in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.

scholarly journals Mitogen-Activated Protein Kinase Phosphatase 1 Disrupts Proinflammatory Protein Synthesis in Endotoxin-Adapted Monocytes

2013 ◽  
Vol 20 (9) ◽  
pp. 1396-1404 ◽  
Author(s):  
Laura Brudecki ◽  
Donald A. Ferguson ◽  
Charles E. McCall ◽  
Mohamed El Gazzar
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Rna Binding ◽  
Multiorgan Failure ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Translational Repressor ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Mitogen Activated Protein

ABSTRACTAutotoxic production of proinflammatory mediators during early sepsis induces excessive inflammation, and their later suppression may limit the immune response. We previously reported that sepsis differentially represses transcription and translation of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) to reprogram sepsis inflammation. This switch is gene specific and plays a crucial role in the clinically relevant syndrome of endotoxin adaptation/tolerance, multiorgan failure, and poor sepsis outcome. To further define the mechanisms responsible for translation disruption that follows inflammation induction, we used THP-1 human promonocytes as a model of Toll-like receptor 4 (TLR4) responses found in sepsis. We showed that phosphorylation-dependent activation of p38 mitogen-activated protein kinase (MAPK) and translation disruption of TNF-α and IL-6 follow increased MAPK phosphatase 1 (MKP-1) expression and that MKP-1 knockdown rephosphorylates p38 and restores the capacity to translate TNF-α and IL-6 mRNAs. We also observed that the RNA-binding protein motif 4 (RBM4), a p38 MAPK target, accumulates in an unphosphorylated form in the cytosol in endotoxin-adapted cells, suggesting that dephosphorylated RBM4 may function as a translational repressor. Moreover, MKP-1 knockdown promotes RBM4 phosphorylation, blocks its transfer from the nucleus to the cytosol, and reverses translation repression. We also found that microRNA 146a (miR-146a) knockdown prevents and miR-146a transfection induces MKP-1 expression, which lead to increases or decreases in TNF-α and IL-6 translation, respectively. We conclude that a TLR4-, miR-146a-, p38 MAPK-, and MKP-1-dependent autoregulatory pathway regulates the translation of proinflammatory genes during the acute inflammatory response by spatially and temporally modifying the phosphorylation state of RBM4 translational repressor protein.

Extracellular signal–regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2175-2182 ◽  
Author(s):  
Amaya Puig-Kröger ◽  
Miguel Relloso ◽  
Oskar Fernández-Capetillo ◽  
Ana Zubiaga ◽  
Augusto Silva ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Protein Kinase ◽  
Intracellular Signaling ◽  
Mannose Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Functional Maturation ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Mitogen Activated Protein

Dendritic cells (DC) are highly specialized antigen-presenting cells that on activation by inflammatory stimuli (eg, tumor necrosis factor α [TNF-α] and interleukin-1β [IL-1β]) or infectious agents (eg, lipopolysaccharide [LPS]), mature and migrate into lymphoid organs. During maturation, DC acquire the capacity to prime and polarize resting naive T lymphocytes. Maturation of monocyte-derived DC (MDDC) is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. This study found that in the presence of the mitogen-activated protein kinase kinase 1–extracellular signal-regulated kinase (ERK) inhibitors PD98059 or U0126, TNF-α– and LPS-induced phenotypic and functional maturation is enhanced. ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor–mediated endocytic activity; nuclear factor-κB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-α. Moreover, PD98059 and U0126 enhanced LPS-triggered production of IL-12 p70. In agreement with the effect of ERK inhibitors, maturation of MDDC was delayed in the presence of serum, an effect that was reversed by U0126. These results indicate that the ERK and p38 MAPK signaling pathways differentially regulate maturation of MDDC and suggest that their relative levels of activation might modulate the initial commitment of naive T-helper (Th) cells toward Th1 or Th2 subsets. The findings also suggest that maturation of MDDC might be pharmacologically modified by altering the relative levels of activation of both intracellular signaling routes.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates Lipopolysaccharide and Tumor Necrosis Factor Alpha Induction of Shiga Toxin 2 Sensitivity in Human Umbilical Vein Endothelial Cells

2007 ◽  
Vol 76 (3) ◽  
pp. 1115-1121 ◽  
Author(s):  
Matthew K. Stone ◽  
Glynis L. Kolling ◽  
Matthew H. Lindner ◽  
Tom G. Obrig
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Umbilical Vein ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Shiga Toxin 2 ◽  
Factor Alpha ◽  
Umbilical Vein Endothelial Cells

ABSTRACTEscherichia coliO157:H7 Shiga toxin 2 (Stx2), one of the causative agents of hemolytic-uremic syndrome, is toxic to endothelial cells, including primary cultured human umbilical vein endothelial cells (HUVEC). This sensitivity of cells to Stx2 can be increased with either lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). The goal of the present study was to identify the intracellular signaling pathway(s) by which LPS and TNF-α sensitize HUVEC to the cytotoxic effects of Stx2. To identify these pathways, specific pharmacological inhibitors and small interfering RNAs were tested with cell viability endpoints. A time course and dose response experiment for HUVEC exposure to LPS and TNF-α showed that a relatively short exposure to either agonist was sufficient to sensitize the cells to Stx2 and that both agonists stimulated intracellular signaling pathways within a short time. Cell viability assays indicated that the p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 and the general protein synthesis inhibitor cycloheximide inhibited both the LPS and TNF-α sensitization of HUVEC to Stx2, while all other inhibitors tested did not inhibit this sensitization. Additionally, SB202190 reduced the cellular globotriaosylceramide content under LPS- and TNF-α-induced conditions. In conclusion, our results show that LPS and TNF-α induction of Stx2 sensitivity in HUVEC is mediated through a pathway that includes p38 MAPK. These results indicate that inhibition of p38 MAPK in endothelial cells may protect a host from the deleterious effects of Stx2.

scholarly journals The molecular mechanism of acute liver injury and inflammatory response induced by Concanavalin A

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Xiaoxiao Liu ◽  
Ting Yu ◽  
Yuzhu Hu ◽  
Longzhen Zhang ◽  
Junnian Zheng ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Liver Injury ◽  
Concanavalin A ◽  
Acute Liver Injury ◽  
Mapk Pathway ◽  
Underlying Mechanism ◽  
Kinase Domain ◽  
Mitogen Activated Protein Kinase ◽  
Tnf Α ◽  
Hepatocyte Death

AbstractAcute liver injury is a common but urgent clinical condition, and its underlying mechanism remains to be further elucidated. Concanavalin A (ConA)-induced liver injury was investigated in the study. Different from the caspase-dependent cell apoptosis in lipopolysaccharide/D-aminogalactose (LPS/D-GalN) induced liver injury, ConA-induced hepatocyte death was independent on caspase. Increased hepatocytic expressions of mixed lineage kinase domain like (MLKL) and receptor-interacting protein kinase 1 (RIPK1), and higher serum concentration of tumor necrosis factor-α (TNF-α) were noticed in mice with ConA-induced liver injury. Inhibition of RIPK1 protein or deletion of MLKL gene could significantly attenuate the acute liver injury and improve mice survival. Besides, the ConA treatment induced severe hepatic inflammation in wide type (WT) mice in comparison with Mlkl−/− mice, suggesting the RIPK1-MLKL-mediated hepatocellular necroptosis might participate in the process of liver injury. Moreover, mitochondrial damage associated molecular patterns (DAMPs) were subsequently released after the hepatocyte death, and further activated the p38 mitogen-activated protein kinase (MAPK) pathway, which could be reduced by deletion or inhibition of Toll-like receptor 9 (TLR9). Taken together, our research revealed that ConA-induced acute liver injury was closely related to TNF-α-mediated cell necroptosis, and inhibiting RIPK1 or deleting MLKL gene could alleviate liver injury in mice. The mitochondrial DNA released by dead hepatocytes further activated neutrophils through TLR9, thus resulting in the exacerbation of liver injury.

scholarly journals Mitogen-Activated Protein Kinase p38 Controls the Expression and Posttranslational Modification of Tristetraprolin, a Regulator of Tumor Necrosis Factor Alpha mRNA Stability

2001 ◽  
Vol 21 (19) ◽  
pp. 6461-6469 ◽  
Author(s):  
Kamal R. Mahtani ◽  
Matthew Brook ◽  
Jonathan L. E. Dean ◽  
Gareth Sully ◽  
Jeremy Saklatvala ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Rna Binding ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
The Stability ◽  
Necrosis Factor ◽  
P38 Pathway

ABSTRACT Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-α) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-α mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-α 3′ untranslated region. The p38 pathway is required for the induction of TNF-α RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-α gene expression at a posttranscriptional level.

scholarly journals Effect of Proinflammatory Cytokines on the Interplay between Roxithromycin, HMR 3647, or HMR 3004 and Human Polymorphonuclear Neutrophils

2000 ◽  
Vol 44 (3) ◽  
pp. 511-521 ◽  
Author(s):  
D. Vazifeh ◽  
A. Bryskier ◽  
M. T. Labro
Keyword(s):  
Protein Kinase ◽  
Proinflammatory Cytokines ◽  
Interleukin 1 ◽  
Inhibitory Effect ◽  
Polymorphonuclear Neutrophils ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α ◽  
Oxidant Production

ABSTRACT Cytokines, the hallmarks of infectious and inflammatory diseases, modify phagocyte activities and thus may interfere with the immunomodulating properties of antibacterial agents. We have investigated whether various proinflammatory cytokines (interleukin 1 [IL-1], IL-6, IL-8, gamma interferon, tumor necrosis factor alpha [TNF-α], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) modify two macrolide properties, i.e., inhibition of oxidant production by polymorphonuclear neutrophils (PMN) and cellular uptake. Roxithromycin and two ketolides, HMR 3647 and HMR 3004, were chosen as the test agents. TNF-α and GM-CSF (but not the other cytokines) decreased the inhibitory effect of HMR 3647 only on oxidant production by PMN. Fifty percent inhibitory concentrations were, however, in the same range in control and cytokine-treated cells (about 60 to 70 μg/ml), suggesting that HMR 3647 acts downstream of the priming effect of cytokines. In contrast, the impairment of oxidant production by roxithromycin and HMR 3004 was unchanged (or increased) in cytokine-treated cells. This result suggests that HMR 3004 (the strongest inhibitory drug, likely owing to its quinoline side chain) and roxithromycin act on a cellular target upstream of cytokine action. In addition, TNF-α and GM-CSF significantly (albeit moderately) impaired (by about 20%) the uptake of the three molecules by PMN. The inhibitory effect of these two cytokines seems to be related to activation of the p38 mitogen-activated protein kinase. Our data also illuminate the mechanism underlying macrolide uptake: protein kinase A- and tyrosine kinase-dependent phosphorylation seems to be necessary for optimal uptake, while protein kinase C activation impairs it. The relevance of our data to the clinical setting requires further investigations, owing to the complexity of the cytokine cascade during infection and inflammation.

scholarly journals The ROCK-Ezrin Signaling Pathway Mediates LPS-Induced Cytokine Production in A549 Cells

2021 ◽  
Author(s):  
Ning Ding ◽  
Huiqing Li ◽  
Baofeng Gao ◽  
Yunlong Lei ◽  
Zengzhen Zhang
Keyword(s):  
Protein Kinase ◽  
Cytokine Production ◽  
Critical Role ◽  
Coiled Coil ◽  
A549 Cells ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Mobility Shift ◽  
Lps Challenge ◽  
Tnf Α

Abstract Background: Ezrin/radixin/moesin proteins (ERMs) are members of the protein 4.1 superfamily and function as linkers that connect the actin cytoskeleton to the plasma membrane of cells. ERMs also play critical role in the Lipopolysaccharide (LPS)-induced inflammatory response. However, the signaling mechanisms involved remain unclear. This study aims to investigate the potential role of the rho-associated coiled-coil containing protein kinase (ROCK) pathway in LPS-induced ezrin phosphorylation and cytokine production in A549 cells. Methods: Cultured A549 cells were treated with LPS. The expression and localization of ezrin in A549 cells were analyzed by Western bloting and immunoflurescence. The activation of RhoA/ROCK was assessed by Western bloting and RhoA activity assays. The interaction of ezrin with Syk and myeloid differentiation factor 88 (MyD88)/IL-1R-associated kinase 1 (IRAK-1) was investigated using co-immunoprecipitation. The activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) was measured with electrophoretic mobility shift assay and Western blotting. ELISA and Western bloting were performed to detect tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and high mobility group box 1 protein (HMGB1) release into the culture supernatant and cellular HMGB1 levels.Results: Here, we show that LPS induced ezrin phosphorylation in a concentration- and time-dependent manner. The blockade of RhoA/ROCK inhibited LPS-induced ezrin phosphorylation and its translocation from the cytoplasm to the cell membrane. Co-immunoprecipitation assays further revealed that ezrin associated with Syk constitutively, but only associated with MyD88/IRAK-1 upon LPS challenge. Moreover, LPS-induced p38 and nuclear NF-κB activation was found to be ezrin dependent. The suppression of ezrin by siRNA or the blockade of ROCK activation with Y-27632 reduced the production of TNF-α, IL-1β, and HMGB1 in response to LPS. Conclusions: Our findings reveal a novel regulatory mechanism involving ezrin in LPS induced the production of pro-inflammatory cytokines, and highlight the importance of the RhoA/ROCK-MyD88/IRAK1-ezrin/Syk axis. Data presented in this manuscript provide novel insights into the signaling pathways activated in A549 cells by LPS.

scholarly journals Wnt/β-catenin signaling contributes to vincristine-induced neuropathic pain

2020 ◽  
pp. 701-710
Author(s):  
C Hu ◽  
Y-T Zhao ◽  
Y-B Cui ◽  
H-H Zhang ◽  
G-L Huang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Protein Kinase ◽  
Critical Role ◽  
Intrathecal Administration ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Limiting Factor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Mitogen Activated Protein

Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the mechanisms underlying CNP remain elusive. In the present study, CNP was induced by repeated intraperitoneal injection of vincristine (VCR) into male C57BL/6J mice. VCR administration caused significant activation of Wnt/β-catenin signaling, which led to the activation of astrocytes, microglia, the release of inflammatory cytokines tumour necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1) and the activation of subsequent mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) signaling pathway in CNP mice. Blocking Wnt/β-catenin signaling by intrathecal administration of the inhibitors of Wnt response (IWR) effectively attenuated VCR-induced neuropathic pain. Furthermore, IWR inhibited the activation of astrocytes, microglia, TNF-α, MCP-1 and MAPK/ERK signaling in the spinal cord, which was triggered by VCR-induced Wnt/β-catenin signaling upregulation. These results suggest that Wnt/β-catenin signaling plays a critical role in VCR-induced neuropathic pain and provides evidence for potential interfering with Wnt/β-catenin signaling to ameliorate VCR-induced neuropathic pain.

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