Dual Action of cAMP-Dependent Protein Kinase on Granulocyte Movement

Ydrenius, Liselotte; Molony, Leslie; Ng-Sikorski, Janet; Andersson, Tommy

doi:10.1006/bbrc.1997.6822

Cited by 33 publications

(26 citation statements)

References 43 publications

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“…As previously reported (6, 38), we find that ET induces a rise in cAMP levels, and under the conditions of our experiments, we observe a Ͼ50-fold rise of cAMP in neutrophils. Our findings are consistent with previous observations of neutrophils and T lymphocytes showing that agents inducing a rise in cAMP can impair actin assembly and chemotaxis (11,18,29,31,39,40). However, a simple quantitative relationship between cAMP levels and alterations in chemotaxis has not been observed, suggesting that additional signal transduction pathways can modify the effects of cAMP (18,29,40).…”

Section: Vol 77 2009 B Anthracis Et Impairs Neutrophil Actin-basedsupporting

confidence: 92%

Bacillus anthracisEdema Toxin Impairs Neutrophil Actin-Based Motility

Szarowicz

During

et al. 2009

Infect Immun

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Inhalation anthrax results in high-grade bacteremia and is accompanied by a delay in the rise of the peripheral polymorphonuclear neutrophil (PMN) count and a paucity of PMNs in the infected pleural fluid and mediastinum. Edema toxin (ET) is one of the major Bacillus anthracis virulence factors and consists of the adenylate cyclase edema factor (EF) and protective antigen (PA). Relatively low concentrations of ET (100 to 500 ng/ml of PA and EF) significantly impair human PMN chemokinesis, chemotaxis, and ability to polarize. These changes are accompanied by a reduction in chemoattractant-stimulated PMN actin assembly. ET also causes a significant decrease in Listeria monocytogenes intracellular actin-based motility within HeLa cells. These defects in actin assembly are accompanied by a >50-fold increase in intracellular cyclic AMP and a >4-fold increase in the phosphorylation of protein kinase A. We have previously shown that anthrax lethal toxin ( Inhalation anthrax can lead to sepsis and death within days if not diagnosed early and treated effectively (21). Epidemiological analyses of the anthrax bioterrorist attacks in 2001 indicated a mean duration of 4.5 days between exposure and symptom onset in the six inhalation anthrax cases for whom the exposure dates could be determined. Analyses of the clinical findings from 10 of the 11 inhalation anthrax cases revealed normal or minimally elevated peripheral polymorphonuclear neutrophil (PMN) counts at the time of hospital admission, despite high-level Bacillus anthracis bacteremia (22). Furthermore, heavily infected pleural fluid demonstrated a paucity of white blood cells. In the fatal cases, mediastinal infection was associated with marked edema and hemorrhage but minimal infiltration by acute inflammatory cells (16). Similarly, experimental inhalation anthrax in monkeys was associated with edema and hemorrhage of the mediastinum and pulmonary interstitium, with absent or modest infiltration by neutrophils (37). These findings suggest impaired delivery of neutrophils to the sites of infection during the early stages of systemic B. anthracis infection.B. anthracis produces three exotoxins, protective antigen (PA), edema factor (EF) and lethal factor (LF), that account for many of the clinical manifestations of this deadly pathogen. PA binds to the widely distributed host cell receptors and then self-associates into heptamers and ushers LF and EF into the cytoplasm of cells (4). The anthrax toxins have been termed AB toxins, PA combined with LF being called lethal toxin (LT), and PA combined with EF termed edema toxin (ET). LF is a Zn 2ϩ -dependent metalloprotease that cleaves mitogenactivated protein kinase kinases (12). EF is a calcium calmodulin-dependent adenylate cyclase, an enzyme that converts ATP to cyclic AMP (cAMP) and pyrophosphate (17) and increases intracellular cAMP levels (26).Neutrophils constitute the first line of defense against bacterial infections. These phagocytic cells are able to quickly crawl, or chemotax, to the site of infection, and def...

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Section: Vol 77 2009 B Anthracis Et Impairs Neutrophil Actin-basedsupporting

confidence: 92%

Bacillus anthracisEdema Toxin Impairs Neutrophil Actin-Based Motility

Szarowicz

During

et al. 2009

Infect Immun

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“…When exposed to fMLP, neutrophils in suspension quickly (within 1-2 minutes) establish a morphological leading edge (Zhelev et al, 2004). The leading edge does not persist, and retracts after stimulation (Fechheimer and Zigmond, 1983;Sklar et al, 1985;Wang et al, 2002;Ydrenius et al, 1997). Attractant stimulation of suspended neutrophils also suffices to accumulate polymerized actin, PIP3 and Rac-GTP, albeit transiently, consistent with the morphological response (Srinivasan et al, 2003;Wang et al, 2002;Xu et al, 2003).…”

Section: Lyn Is Not Required For the 'Frontness' Signalsmentioning

confidence: 69%

The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL–C3G complex and activating Rap1 at the leading edge

Kapoor

Cook

et al. 2011

Journal of Cell Science

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Research Article 2153 IntroductionCell migration has been conceptualized as a cycle (Ridley et al., 2003). After a stimulus, cells polymerize actin at the front to initiate protrusions. These protrusions are stabilized by adhering to extracellular matrix (ECM) molecules (adhesion). Adhesions serve as traction sites as the cell moves forward, and are disassembled at the rear, allowing the cell to detach and retract. In general, strategies for single-cell migration can be classified into two patterns: amoeboid movement and mesenchymal migration (Friedl, 2004). Slow-moving mesenchymal cells (e.g. fibroblasts) often adopt a spindle-shaped morphology and adhere via large integrin-mediated plaque-like structures called focal adhesions. By contrast, fastmoving cells (e.g. neutrophils) use amoeboid movement associated with fast deformability and highly polarized morphology, and move more rapidly. Unlike the mesenchymal migration paradigm, large focal adhesions seen in slow moving fibroblasts and stress fibers are not detected in these cells (Friedl, 2004), suggesting fundamental differences between amoeboid and mesenchymal cell adhesions; however, integrin-mediated adhesion is necessary for persistent cell migration (Ley et al., 2007).When exposed to chemoattractants, neutrophils polarize and initiate polymerization of actin at the leading edge (pseudopod) to provide the protrusive force. Primary neutrophils and neutrophillike cells have complex signaling pathways that control formation of their front and back. A 'frontness' pathway containing Rac, the lipid products of phosphoinositide-3-kinases (PI3Ks) and polymerized actin organizes the leading edge of neutrophils, whereas the 'backness' signals, including Rho, p160-ROCK and myosin II, lead to contraction of actin-myosin complexes at the trailing edge, causing cells to de-adhere (Srinivasan et al., 2003;Wang et al., 2002;Xu et al., 2003).Despite these advances, little is known about the regulation of cell-ECM adhesion during chemotaxis. Frontness and backness responses per se do not entirely account for the persistent polarity and motility of neutrophils when they are exposed to chemoattractants. Indeed, chemoattractant stimulation of neutrophils in suspension (i.e. without cell adhesion to the substrate) only causes transient membrane extension, in sharp contrast to cells stimulated on substrates, which polarize and migrate persistently (Srinivasan et al., 2003;Wang et al., 2002;Xu et al., 2003). In circulating neutrophils 2 integrins (CD18) are highly expressed and mediate the interactions of neutrophils with endothelial cells. The importance of 2-integrin-mediated adhesion in neutrophil chemotaxis is highlighted by patients with leukocyte adhesion deficiency (LAD), who have decreased numbers of neutrophils at the sites of infection and inflammation (Bunting et al., 2002). These findings imply a crucial role of cell-substrate adhesion in the regulation of neutrophil polarity and motility.To dissect the molecular program that governs adhesion of the neutrophil lea...

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“…Alternatively, rapid inhibition of protein phosphatase activity can also contribute to p38 MAPK activation in the absence of MKK3/6 activation (44,49). Indeed, inhibition of protein tyrosine phosphatase activity may occur in a cAMP-dependent protein kinase-dependent manner (50); this is intriguing because cAMP-dependent protein kinase plays a critical role in the cellular response to chemoattractants (51) such as plasmin (9). However, the precise nature of this early phase of p38 MAPK activation in human monocytes remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

The Serine Protease Plasmin Triggers Expression of MCP-1 and CD40 in Human Primary Monocytes via Activation of p38 MAPK and Janus Kinase (JAK)/STAT Signaling Pathways

Burýšek

Syrovets

Simmet

2002

Journal of Biological Chemistry

153

148

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The mechanism of proinflammatory activation of human monocytes by plasmin is unknown. Here we demonstrate that in human primary monocytes, plasmin stimulates mitogen-activated protein kinase (MAPK) signaling via phosphorylation of MAPK kinase 3/6 (MKK3/6) and p38 MAPK that triggers subsequent DNA binding of transcription factor activator protein-1 (AP-1). The AP-1 complex contained phosphorylated c-Jun and ATF2, and its DNA binding activity was blocked by the p38 MAPK inhibitor SB203580. In addition, plasmin elicits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, as detected by phosphorylation of JAK1 tyrosine kinase and STAT1 and STAT3 proteins. Plasmin-induced DNA binding of STAT1 and STAT3 was blocked by SB203580 and AG490, inhibitors of p38 MAPK and JAK, respectively, but not by U0126, an inhibitor of MKK1/2. DNA binding of NF-B remained unaffected by any of these inhibitors. The plasmin-induced signaling led to expression of monocyte chemoattractant protein-1 (MCP-1) and CD40, which required activation of both p38 MAPK and JAK/ STAT signaling pathways. Additionally, signaling through both p38 MAPK and JAK is involved in the plasmin-mediated monocyte migration, whereas the formylmethionylleucylphenylalanine-induced chemotaxis remained unaffected. Taken together, our data demonstrate a novel function of the serine protease plasmin in a proinflammatory signaling network.

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Dual Action of cAMP-Dependent Protein Kinase on Granulocyte Movement

Cited by 33 publications

References 43 publications

Bacillus anthracisEdema Toxin Impairs Neutrophil Actin-Based Motility

Bacillus anthracisEdema Toxin Impairs Neutrophil Actin-Based Motility

The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL–C3G complex and activating Rap1 at the leading edge

The Serine Protease Plasmin Triggers Expression of MCP-1 and CD40 in Human Primary Monocytes via Activation of p38 MAPK and Janus Kinase (JAK)/STAT Signaling Pathways

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