HIV gp120 induces cardiac dysfunction in vivo associated with p38 MAP kinase phosphorylation and iNOS protein synthesis

SummaryWe investigated similarities in the signaling pathways elicited by the F2 isoprostane 8-iso-PGF2α and by low doses of U46619 to induce platelet activation. Both 0.01-0.1 µmol/L U46619 and 0.01-1 µmol/L 8-isoPGF2α triggered shape change and filopodia extension, as well as adhesion to immobilized fibrinogen of washed platelets. At these doses the two platelet agonists failed to trigger secretion and aggregation, which were however induced by higher doses of U46619 (0.1-1 µmol/L). SB203580 (1-10 µmol/L), a specific inhibitor of the p38 mitogen activated protein (MAP) kinase blunted platelet shape change and adhesion induced by 0.05-1 µmol/L 8-iso-PGF2α and by 0.01 µmol/L U46619. These platelet responses were also inhibited by 20 µmol/L cytochalasin D, an inhibitor of actin polymerization, and 50 µmol/L piceatannol, an inhibitor of the Syk tyrosine kinases. Both 8-iso-PGF2α and U46619-induced p38 MAP kinase phosphorylation in suspended platelets and this was inhibited by piceatannol, indicating that Syk activation occurs upstream p38 MAP kinase phosphorylation. These findings suggest that the signaling pathway triggered by both 8-iso-PGF2α and low concentrations of U46619 to induce platelet adhesion and shape change implicates Syk, the p38 MAP kinase, and actin polymerization.

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Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3

Blood ◽

10.1182/blood-2008-08-172767 ◽

2009 ◽

Vol 113 (15) ◽

pp. 3512-3519 ◽

Cited By ~ 41

Author(s):

Roberta Caruso ◽

Carmine Stolfi ◽

Massimiliano Sarra ◽

Angelamaria Rizzo ◽

Massimo C. Fantini ◽

...

Keyword(s):

Map Kinase ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Human Peripheral Blood ◽

Serum Levels ◽

Cell Types ◽

P38 Map Kinase ◽

Negative Regulator ◽

Therapeutic Implications

Abstract IL-25, a member of the IL-17 cytokine family, is known to enhance Th2-like responses associated with increased serum levels of IgE, IgG1, IgA, blood eosinophilia, and eosinophilic infiltrates in various tissues. However, IL-25 also abrogates inflammatory responses driven by Th17 cells. However, the cell types that respond to IL-25 and the mechanisms by which IL-25 differentially regulates immune reactions are not well explored. To identify potential targets of IL-25, we initially examined IL-25 receptor (IL-25R) in human peripheral blood cells. IL-25R was predominantly expressed by CD14+ cells. We next assessed the functional role of IL-25 in modulating the response of CD14+ cells to various inflammatory signals. CD14+ cells responded to IL-25 by down-regulating the synthesis of inflammatory cytokines induced by toll-like receptor (TLR) ligands and inflammatory cytokines. Inhibition of cytokine response by IL-25 occurred via a p38 Map kinase–driven Socs-3–dependent mechanism. In vivo, IL-25 inhibited monocyte-derived cytokines and protected against LPS-induced lethal endotoxemia in mice. These data indicate that IL-25 is a negative regulator of monocyte proinflammatory cytokine responses, which may have therapeutic implications.

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Positive feedback induces switch between distributive and processive phosphorylation of Hog1

10.1101/2020.05.05.078352 ◽

2020 ◽

Author(s):

Maximilian Mosbacher ◽

Sung Sik Lee ◽

Matthias Peter ◽

Manfred Claassen

Keyword(s):

Map Kinase ◽

Positive Feedback ◽

Ode Models ◽

Cellular Decision Making ◽

Activation Data ◽

Best Fitting ◽

Phosphorylation Mechanism ◽

Kinase Phosphorylation ◽

Multiple Conditions

SummaryCellular decision making often builds on ultrasensitive MAPK pathways. The phosphorylation mechanism of MAP kinase has so far been described as either distributive or processive, with distributive mechanisms generating ultrasensitivity in theoretical analyses. However, the in vivo mechanism of MAP kinase phosphorylation and its regulation by feedback loops remain unclear. We thus characterized the regulation of the MAP kinase Hog1 in Saccharomyces cerevisiae, which is transiently activated in response to hyperosmolarity. Specifically, we combined Hog1 activation data from different modalities and multiple conditions. We constructed ODE models with different pathway topologies, which were then assessed via parameter estimation and model selection. Interestingly, our best fitting model switches between distributive and processive phosphorylation behavior via a positive feedback loop targeting the MAP kinase-kinase Pbs2. Simulations further suggest that this mixed mechanism is required not only for full sensitivity to stimuli, but also to ensure robustness to different perturbations.

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Coupling of M2 muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.278.3.g429 ◽

2000 ◽

Vol 278 (3) ◽

pp. G429-G437 ◽

Cited By ~ 21

Author(s):

Amy K. Cook ◽

Michael Carty ◽

Cherie A. Singer ◽

Ilia A. Yamboliev ◽

William T. Gerthoffer

Keyword(s):

Smooth Muscle ◽

Map Kinase ◽

Muscarinic Receptors ◽

Map Kinases ◽

Kinase Inhibitor ◽

Receptor Activation ◽

Inhibitory Effect ◽

Subsequent Treatment ◽

P38 Map Kinase

Coupling of M2 and M3 muscarinic receptors to activation of mitogen-activated protein (MAP) kinases and phosphorylation of caldesmon was studied in canine colonic smooth muscle strips in which M3 receptors were selectively inactivated by N, N-dimethyl-4-piperidinyl diphenylacetate (4-DAMP) mustard (40 nM). ACh elicited activation of extracellular signal-regulated kinase (ERK) 1, ERK2, and p38 MAP kinases in control muscles and increased phosphorylation of caldesmon (Ser789), a putative downstream target of MAP kinases. Alkylation of M3 receptors with 4-DAMP had only a modest inhibitory effect on ERK activation, p38 MAP kinase activation, and caldesmon phosphorylation. Subsequent treatment with 1 μM AF-DX 116 completely prevented activation of ERK and p38 MAP kinase and prevented caldesmon phosphorylation. Caldesmon phosphorylation was blocked by the MAP kinase/ERK kinase inhibitor PD-98509 but not by the p38 MAP kinase inhibitor SB-203580. These results indicate that colonic smooth muscle M2 receptors are coupled to ERK and p38 MAP kinases. Activation of ERK, but not p38 MAP kinases, results in phosphorylation of caldesmon in vivo, which is a novel function for M2receptor activation in smooth muscle.

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p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes

AJP Cell Physiology ◽

10.1152/ajpcell.00059.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. C1-C7 ◽

Cited By ~ 42

Author(s):

Hong Kan ◽

Zirong Xie ◽

Mitchell S. Finkel

Keyword(s):

Map Kinase ◽

Cardiac Myocytes ◽

Myocardial Dysfunction ◽

Negative Inotropic Effect ◽

P38 Map Kinase ◽

Neonatal Rat ◽

Inotropic Effect ◽

Kinase Activation ◽

Hiv Gp120 ◽

Sb 203580

Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca2+concentration ([Ca2+]i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased [Ca2+]iwithin 5 min and then depressed FS without a decrease in [Ca2+]iby 20–60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 μM) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 μM) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 μM) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.

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