MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages

2010 ◽  
Vol 425 (3) ◽  
pp. 595-602 ◽  
Author(s):  
Joanne Darragh ◽  
Olga Ananieva ◽  
Alan Courtney ◽  
Suzanne Elcombe ◽  
J. Simon C. Arthur
Keyword(s):  
Interleukin 1 ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Extracellular Signal Regulated Kinase ◽  
Il Interleukin ◽  
Naturally Occurring ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

The activity of the pro-inflammatory cytokine IL (interleukin)-1 is closely regulated in vivo via a variety of mechanisms, including both the control of IL-1 production and secretion as well as naturally occurring inhibitors of IL-1 function, such as IL-1ra (IL-1 receptor antagonist). IL-1ra is homologous with IL-1, and is able to bind but not activate the IL-1 receptor. IL-1ra can be produced by a variety of cell types, and its production is stimulated by inflammatory signals. In the present study, we show that in macrophages the TLR (Toll-like receptor)-mediated induction of IL-1ra from both its proximal and distal promoters involves the p38 and ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) cascades. In addition, we show that MSK1 and 2 (mitogen- and stress-activated kinase 1 and 2), kinases activated by either ERK1/2 or p38 in vivo, are required for the induction of both IL-1ra mRNA and protein. MSKs regulate IL-1ra transcription via both IL-10-dependent and -independent mechanisms in cells. Consistent with this, knockout of MSK in mice was found to result in a decrease in IL-1ra production following LPS (lipopolysaccharide) injection. MSKs therefore act as important negative regulators of inflammation following TLR activation.

scholarly journals p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli

2004 ◽  
Vol 15 (2) ◽  
pp. 922-933 ◽  
Author(s):  
Almudena Porras ◽  
Susana Zuluaga ◽  
Emma Black ◽  
Amparo Valladares ◽  
Alberto M. Alvarez ◽  
...  
Keyword(s):  
Map Kinase ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Survival Pathways ◽  
Proapoptotic Protein ◽  
Extracellular Signal ◽  
Survival Pathway ◽  
Mitogen Activated Protein

p38α mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38α knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38α are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38α-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38α also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38α. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38α-/- cells. Thus, p38α seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.

Delivery of Sorafenib and Metformin Against Hepatocellular Carcinoma with Amphiphilic Polypeptide-based Micelles

2021 ◽  
Author(s):  
Lanqing Cao ◽  
Guangmeng Xu ◽  
Hongyu He ◽  
Jiannan Li
Keyword(s):  
Mapk Pathway ◽  
Synergistic Effects ◽  
Mitogen Activated Protein Kinase ◽  
High Recurrence Rate ◽  
Extracellular Signal Regulated Kinase ◽  
Cycle Arrest ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Poly Ethylene

Abstract Hepatoma is a common clinical disease with poor prognosis and a high recurrence rate. Chemotherapy is important for hepatoma treatment because only a small amount of hepatoma patients are suitable for local resection, and the effects of transarterial chemoembolization (TACE) are unsatisfactory. But many limitations restrict further application of chemotherapy. In this study, sorafenib (Sor) and metformin (Met) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Glu-co-Phe)) micelles were developed. Sor is a common molecular target agent which can inhibit the mitogen-activated protein kinase (MAPK) pathway to treat hepatoma clinically. Met can also regulate the MAPK pathway and inhibit the expression of the phosphorylated extracellular signal-regulated kinase (p-ERK). Moreover, both Sor and Met play important roles in cell cycle arrest. The integration of these two drugs aims to achieve synergistic effects against hepatoma. The micelles can be targeted to cancer cells and possess longer blood circulation time. The two agents can be released rapidly in the tumor sites. Both orthotopic and patient-derived xenograft (PDX) hepatoma models were developed to analyze the treatment efficacy of the Sor and Met loaded micelles. The in vivo study showed that the micelles can prevent hepatoma progression by inhibiting the expressions of p-ERK and cyclin D1. This study indicated that the Sor/Met-loaded micelles are suitable for hepatoma treatment.

VEGFD regulates blood vascular development by modulating SOX18 activity

Blood ◽  
2014 ◽  
Vol 123 (7) ◽  
pp. 1102-1112 ◽  
Author(s):  
Tam Duong ◽  
Katarzyna Koltowska ◽  
Cathy Pichol-Thievend ◽  
Ludovic Le Guen ◽  
Frank Fontaine ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Vascular Development ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Key Points ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

Key Points Haploinsufficiency of Sox18 reveals an important role for VEGFD in regulating blood vascular development in vivo in vertebrates. VEGFD acts through mitogen-activated protein kinase kinase–extracellular signal-regulated kinase to modulate the activity and nuclear concentration of endothelial-specific transcription factor SOX18.

scholarly journals Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
N. Ronkina ◽  
K. Schuster-Gossler ◽  
F. Hansmann ◽  
H. Kunze-Schumacher ◽  
I. Sandrock ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Knockout Mice ◽  
Germ Line ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase 6/extracellular signal-regulated kinase 3 (MAPK6/ERK3) is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a lacZ insertion in exon 2 due to pulmonary dysfunction and by defects in function, activation, and positive selection of T cells. To study the role of ERK3 in vivo, we generated mice carrying a conditional Erk3 allele with exon 3 flanked by loxP sites. Loss of ERK3 protein was validated after deletion of Erk3 in the female germ line using zona pellucida 3 (Zp3)-cre and a clear reduction of the protein kinase MK5 is detected, providing the first evidence for the existence of the ERK3/MK5 signaling complex in vivo. In contrast to the previously reported Erk3 knockout phenotype, these mice are viable and fertile and do not display pulmonary hypoplasia, acute respiratory failure, abnormal T-cell development, reduction of thymocyte numbers, or altered T-cell selection. Hence, ERK3 is dispensable for pulmonary and T-cell functions. The perinatal lethality and lung and T-cell defects of the previous ERK3 knockout mice are likely due to ERK3-unrelated effects of the inserted lacZ-neomycin resistance cassette. The knockout mouse of the closely related atypical MAPK ERK4/MAPK4 is also normal, suggesting redundant functions of both protein kinases.

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