scholarly journals Activation of p38 Mitogen-Activated Protein Kinase In Vivo Selectively Induces Apoptosis of CD8+ but Not CD4+ T Cells

2000 ◽  
Vol 20 (3) ◽  
pp. 936-946 ◽  
Author(s):  
Chris Merritt ◽  
Hervé Enslen ◽  
Nicole Diehl ◽  
Dietrich Conze ◽  
Roger J. Davis ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Map Kinase ◽  
Molecular Mechanisms ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein ◽  
Map Kinase Pathway ◽  
Kinase Pathway

ABSTRACT CD4+ and CD8+ T cells play specific roles during an immune response. Different molecular mechanisms could regulate the proliferation, death, and effector functions of these two subsets of T cells. The p38 mitogen-activated protein (MAP) kinase pathway is induced by cytokines and environmental stress and has been associated with cell death and cytokine expression. Here we report that activation of the p38 MAP kinase pathway in vivo causes a selective loss of CD8+ T cells due to the induction of apoptosis. In contrast, activation of p38 MAP kinase does not induce CD4+T-cell death. The apoptosis of CD8+ T cells is associated with decreased expression of the antiapoptotic protein Bcl-2. Regulation of the p38 MAP kinase pathway in T cells is therefore essential for the maintenance of CD4/CD8 homeostasis in the peripheral immune system. Unlike cell death, gamma interferon production is regulated by the p38 MAP kinase pathway in both CD4+ and CD8+ T cells. Thus, specific aspects of CD4+and CD8+ T-cell function are differentially controlled by the p38 MAP kinase signaling pathway.

scholarly journals Activation of the p38 Mitogen-Activated Protein Kinase Pathway Arrests Cell Cycle Progression and Differentiation of Immature Thymocytes in Vivo

2000 ◽  
Vol 191 (2) ◽  
pp. 321-334 ◽  
Author(s):  
Nicole L. Diehl ◽  
Hervé Enslen ◽  
Karen A. Fortner ◽  
Chris Merritt ◽  
Nate Stetson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Specific Gene ◽  
Thymocyte Development ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

The development of T cells in the thymus is coordinated by cell-specific gene expression programs that involve multiple transcription factors and signaling pathways. Here, we show that the p38 mitogen-activated protein (MAP) kinase signaling pathway is strictly regulated during the differentiation of CD4−CD8− thymocytes. Persistent activation of p38 MAP kinase blocks fetal thymocyte development at the CD25+CD44− stage in vivo, and results in the lack of T cells in the peripheral immune system of adult mice. Inactivation of p38 MAP kinase is required for further differentiation of these cells into CD4+CD8+ thymocytes. The arrest of cell cycle in mitosis is partially responsible for the blockade of differentiation. Therefore, the p38 MAP kinase pathway is a critical regulatory element of differentiation and proliferation during the early stages of in vivo thymocyte development.

Inhibition of the p38 MAP kinase pathway destabilizes smooth muscle length during physiological loading

2002 ◽  
Vol 282 (5) ◽  
pp. L1117-L1121 ◽  
Author(s):  
Oren J. Lakser ◽  
Robert P. Lindeman ◽  
Jeffrey J. Fredberg
Keyword(s):  
Smooth Muscle ◽  
Map Kinase ◽  
Muscle Length ◽  
P38 Map Kinase ◽  
Force Fluctuations ◽  
Physiological Loading ◽  
Mitogen Activated Protein ◽  
Equilibrium Length ◽  
Map Kinase Pathway ◽  
Kinase Pathway

We tested the hypothesis that mechanical plasticity of airway smooth muscle may be mediated in part by the p38 mitogen-activated protein (MAP) kinase pathway. Bovine tracheal smooth muscle (TSM) strips were mounted in a muscle bath and set to their optimal length, where the active force was maximal (Fo). Each strip was then contracted isotonically (at 0.32 Fo) with ACh (maintained at 10−4 M) and allowed to shorten for 180 min, by which time shortening was completed and the static equilibrium length was established. To simulate the action of breathing, we then superimposed on this steady distending force a sinusoidal force fluctuation with zero mean, at a frequency of 0.2 Hz, and measured incremental changes in muscle length. We found that TSM strips incubated in 10 μM SB-203580-HCl, an inhibitor of the p38 MAP kinase pathway, demonstrated a greater degree of fluctuation-driven lengthening than did control strips, and upon removal of the force fluctuations they remained at a greater length. We also found that the force fluctuations themselves activated the p38 MAP kinase pathway. These findings are consistent with the hypothesis that inhibition of the p38 MAP kinase pathway destabilizes muscle length during physiological loading.

scholarly journals A Chemical Genetics Screen Reveals Influence of p38 Mitogen-Activated Protein Kinase and Autophagy on Phagosome Development and Intracellular Replication ofBrucella neotomaein Macrophages

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
Yoon-Suk Kang ◽  
James E. Kirby
Keyword(s):  
Map Kinase ◽  
Host Cell ◽  
Legionella Pneumophila ◽  
Chemical Genetics ◽  
P38 Map Kinase ◽  
Intracellular Replication ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
Map Kinase Pathway ◽  
Kinase Pathway

ABSTRACTBrucellais an intracellular bacterial pathogen that causes chronic systemic infection in domesticated livestock and poses a zoonotic infectious risk to humans. The virulence ofBrucellais critically dependent on its ability to replicate and survive within host macrophages.Brucellamodulates host physiological pathways and cell biology in order to establish a productive intracellular replicative niche. Conversely, the host cell presumably activates pathways that limit infection. To identify host pathways contributing to this yin and yang during host cell infection, we performed a high-throughput chemical genetics screen of known inhibitors and agonists of host cell targets to identify host factors that contribute to intracellular growth of the model pathogenBrucella neotomae. Using this approach, we identified the p38 mitogen-activated protein (MAP) kinase pathway and autophagy machinery as both a linchpin and an Achilles’ heel inB. neotomae’s ability to coopt host cell machinery and replicate within macrophages. Specifically,B. neotomaeinduced p38 MAP kinase phosphorylation and autophagy in a type IV secretion system-dependent fashion. Both p38 MAP kinase stimulation and an intact autophagy machinery in turn were required for phagosome maturation and intracellular replication. These findings contrasted with those forLegionella pneumophila, where chemical inhibition of the p38 MAP kinase pathway and autophagy factor depletion failed to block intracellular replication. Therefore, results from a chemical genetics screen suggest that intersections of the MAP kinase pathways and autophagy machinery are critical components ofBrucella’s intracellular life cycle.

scholarly journals Control of Borrelia burgdorferi-Specific CD4+-T-Cell Effector Function by Interleukin-12- and T-Cell Receptor-Induced p38 Mitogen-Activated Protein Kinase Activity

2006 ◽  
Vol 74 (10) ◽  
pp. 5713-5717 ◽  
Author(s):  
Michael N. Hedrick ◽  
Chris M. Olson ◽  
Dietrich B. Conze ◽  
Tonya C. Bates ◽  
Mercedes Rincón ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Map Kinase ◽  
Kinase Activity ◽  
Cell Receptor ◽  
P38 Map Kinase ◽  
Interleukin 12 ◽  
Th1 Response ◽  
Mitogen Activated Protein ◽  
Ifn Γ

ABSTRACT Infection with Borrelia burgdorferi, the causative agent of Lyme disease, results in a Th1 response and proinflammatory cytokine production. Mice deficient for MKK3, an upstream activator of p38 mitogen-activated protein (MAP) kinase, develop a lower Th1 response and exhibit an impaired ability to produce proinflammatory cytokines upon infection with the spirochete. We investigated the contribution of p38 MAP kinase activity in gamma interferon (IFN-γ) production in CD4+ T cells in response to specific antigen through T-cell receptor (TCR)- and interleukin-12 (IL-12)-mediated signals. The specific inhibition of p38 MAP kinase in T cells and the administration of a pharmacological inhibitor of the kinase during the course of infection with the spirochete resulted in reduced levels of IFN-γ in the sera of infected mice. Our results also demonstrate that although p38 MAP kinase activity is not required for the differentiation of B. burgdorferi-specific CD4+ T cells, the production of IFN-γ by Th1 effector cells is regulated by the kinase. Both TCR engagement and IL-12 induced the production of the Th1 cytokine through the activation of the p38 MAP kinase pathway. Thus, the inhibition of this pathway in vitro resulted in decreased levels of IFN-γ during restimulation of B. burgdorferi-specific T cells in response to anti-CD3 and IL-12 stimulation. These results clarify the specific contribution of the p38 MAP kinase in the overall immune response to the spirochete and its role in the effector function of B. burgdorferi-specific T cells.

scholarly journals The MADD-3 LAMMER Kinase Interacts with a p38 MAP Kinase Pathway to Regulate the Display of the EVA-1 Guidance Receptor in Caenorhabditis elegans

PLoS Genetics ◽  
2016 ◽  
Vol 12 (4) ◽  
pp. e1006010 ◽  
Author(s):  
Serena A. D’Souza ◽  
Luckshi Rajendran ◽  
Rachel Bagg ◽  
Louis Barbier ◽  
Derek M. van Pel ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Caenorhabditis Elegans ◽  
Map Kinase ◽  
Motor Neurons ◽  
Leading Edge ◽  
P38 Map Kinase ◽  
Endosomal Trafficking ◽  
Guidance Cue ◽  
Map Kinase Pathway ◽  
Kinase Pathway

The proper display of transmembrane receptors on the leading edge of migrating cells and cell extensions is essential for their response to guidance cues. We previously discovered that MADD-4, which is an ADAMTSL secreted by motor neurons in Caenorhabditis elegans, interacts with an UNC-40/EVA-1 co-receptor complex on muscles to attract plasma membrane extensions called muscle arms. In nematodes, the muscle arm termini harbor the post-synaptic elements of the neuromuscular junction. Through a forward genetic screen for mutants with disrupted muscle arm extension, we discovered that a LAMMER kinase, which we call MADD-3, is required for the proper display of the EVA-1 receptor on the muscle’s plasma membrane. Without MADD-3, EVA-1 levels decrease concomitantly with a reduction of the late-endosomal marker RAB-7. Through a genetic suppressor screen, we found that the levels of EVA-1 and RAB-7 can be restored in madd-3 mutants by eliminating the function of a p38 MAP kinase pathway. We also found that EVA-1 and RAB-7 will accumulate in madd-3 mutants upon disrupting CUP-5, which is a mucolipin ortholog required for proper lysosome function. Together, our data suggests that the MADD-3 LAMMER kinase antagonizes the p38-mediated endosomal trafficking of EVA-1 to the lysosome. In this way, MADD-3 ensures that sufficient levels of EVA-1 are present to guide muscle arm extension towards the source of the MADD-4 guidance cue.

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