Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression

2009 ◽  
Vol 105 (3) ◽  
pp. 389-397 ◽  
Author(s):  
Florian H. Seeger ◽  
Daniel Sedding ◽  
Alexander C. Langheinrich ◽  
Judith Haendeler ◽  
Andreas M. Zeiher ◽  
...  
Keyword(s):  
Map Kinase ◽  
Disease Progression ◽  
Functional Activity ◽  
P38 Map Kinase ◽  
Atherosclerotic Disease ◽  
Vasculogenic Cells

Abstract 3461: Inhibition of the p38 MAP Kinase in Vivo Improves Number and Functional Activity of Progenitor Cells and Reduces Atherosclerotic Disease Progression

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Florian Seeger ◽  
Daniel Sedding ◽  
Alexander C Langheinrich ◽  
Tina Rasper ◽  
Andreas M Zeiher ◽  
...  
Keyword(s):  
Risk Factors ◽  
Metabolic Syndrome ◽  
Map Kinase ◽  
Disease Progression ◽  
Progenitor Cells ◽  
Functional Activity ◽  
Progenitor Cell ◽  
P38 Map Kinase ◽  
Kinase Inhibition

Initial trials suggest that bone marrow-derived mononuclear cells (BMC) and ex vivo expanded endothelial progenitor cells (EPC) augment neovascularisation in patients after myocardial infarction. However, patients with cardiovascular risk factors show reduced number and impaired functional activity of EPC and increased activity of the p38 MAP kinase. Therefore, we examined the effect of p38 MAP kinase inhibition on progenitor cells in an in vivo model of metabolic syndrome and atherosclerosis. Consistent with the impairment of EPC by risk factors for coronary artery disease in humans, Lepr db mice exhibited a significantly lower number of EPC (sca-1 + /flk-1 + cells) and an increased number of inflammatory cells (Gr1 + /CD45 + cells) compared to their wild type littermates (0.05±0.07% vs. 1.6±1.1%, and 48.2±11% vs. 23.4±5.9%, respectively). Treatment of Lepr db mice with the p38 inhibitor SB203580 significantly increased the number of sca-1 + /flk-1 + cells (29±7 -fold increase) and lowered the number of GR1 + /CD45 + cells (69±11% of Lepr db mice). Moreover, both, reduced EPC colony forming activity (60±6 % of wt), and impaired BMC invasion capacity (58±13% of wt) were significantly improved in Lepr db mice by p38 inhibition. Finally, treatment of ApoE −/− mice with the SB203580 for 4 months reduced atheromatous lesion size by 51±3% (p<0.05). This study provides first evidence that p38 MAP kinase inhibition with SB203580 improves the impaired progenitor cell number and functional activity in an animal model of metabolic syndrome. Improvement of progenitor cell function is associated with reduction of atheroscle-rotic disease progression in ApoE −/− mice.

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

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3512-3519 ◽  
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.

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

2000 ◽  
Vol 278 (3) ◽  
pp. G429-G437 ◽  
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.

scholarly journals SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation

Oncotarget ◽  
2015 ◽  
Vol 6 (14) ◽  
pp. 12421-12435 ◽  
Author(s):  
Nadia Casini ◽  
Iris Maria Forte ◽  
Gianmarco Mastrogiovanni ◽  
Francesca Pentimalli ◽  
Adriano Angelucci ◽  
...  
Keyword(s):  
Cell Growth ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Src Family Kinase ◽  
Rhabdomyosarcoma Cell

Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway

2000 ◽  
Vol 278 (6) ◽  
pp. H1899-H1907 ◽  
Author(s):  
Ilia A. Yamboliev ◽  
Jason C. Hedges ◽  
Jack L.-M. Mutnick ◽  
Leonard P. Adam ◽  
William T. Gerthoffer
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Map Kinase ◽  
Map Kinases ◽  
Contractile Response ◽  
P38 Map Kinase ◽  
Hsp27 Phosphorylation ◽  
Sb 203580

Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle by using inhibitors of both MAP kinase pathways. In intact smooth muscle, PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.

scholarly journals Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing

2020 ◽  
Author(s):  
Emma S Chambers ◽  
Milica Vukmanovic-Stejic ◽  
Barbara B Shih ◽  
Hugh Trahair ◽  
Priya Subramanian ◽  
...  
Keyword(s):  
Older Adults ◽  
Prostaglandin E2 ◽  
Map Kinase ◽  
Kinase Inhibitor ◽  
Tissue Injury ◽  
P38 Map Kinase ◽  
Prostaglandin E ◽  
Varicella Zoster ◽  
Cutaneous Immunity

AbstractAgeing results in a decline in immune function. We showed previously that healthy older humans (>65 years old) have reduced antigen-specific cutaneous immunity to varicella zoster virus (VZV) antigen challenge. This was associated with p38 MAP kinase driven inflammation that was induced by mild tissue injury caused by the injection of the antigen itself. Here we show that non-specific injury induced by injection of air or saline into the skin of older adults recruits CCR2+CD14+ monocytes by CCL2 produced by senescent fibroblasts. These monocytes reduced TRM proliferation via secretion of prostaglandin E2 (PGE2). Pre-treatment with a p38-MAPK inhibitor (Losmapimod) in older adults in vivo significantly decreased CCL2 expression, recruitment of monocyte into the skin, COX2 expression and PGE2 production. This enhanced the VZV response in the skin. Therefore, local inflammation arising from interaction between senescent cells and monocytes leads to immune decline in the skin during ageing, a process that can be reversed.SummaryInflammation resulting from tissue injury blocks antigen-specific cutaneous immunity during ageing. Monocytes recruited to the skin inhibit TRM function through COX2-derived prostaglandin E2 production. Blocking inflammation and resulting prostaglandin E2 production with a p38-MAP kinase inhibitor significantly enhances cutaneous antigen-specific responses.

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