Platelet factor 4/CXCL4-stimulated human monocytes induce apoptosis in endothelial cells by the release of oxygen radicals

Woller, Geske; Brandt, Ernst; Mittelstädt, Jessica; Rybakowski, C.; Petersen, Frank

doi:10.1189/jlb.0907592

Cited by 48 publications

(40 citation statements)

References 49 publications

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“…25 In vitro studies have shown that PF4 can stimulate monocytes to cause apoptosis of endothelial cells. 38 More recently, PF4 has been found to stimulate release of inflammatory mediators from parenchymal cells, such as vascular smooth muscle cells. 39 Serotonin was also detected in large quantities in the allografts.…”

Section: Discussionmentioning

confidence: 99%

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Kuo

Fan²,

Dvorina³

et al. 2015

Journal of the American Society of Nephrology

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Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100-to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.

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Section: Discussionmentioning

confidence: 99%

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Kuo

Fan²,

Dvorina³

et al. 2015

Journal of the American Society of Nephrology

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“…Human natural CXCL4 was purified in our laboratory from release supernatants of thrombin-stimulated platelets, as described previously [39]. Antibodies directed against Erk1 p44 (serum K-23; cross-reactive to Erk2 p42), and phospho-Erk (clone E-4) were purchased from Santa Cruz Biotechnology (Heidelberg, Germany), while anti-SphK1 antiserum was purchased from ABGENT (Bioggio-Lugano, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

CXCL4‐induced monocyte survival, cytokine expression, and oxygen radical formation is regulated by sphingosine kinase 1

Kasper

Winoto-Morbach²,

Mittelstädt

et al. 2010

Eur J Immunol

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Human monocytes respond to a variety of stimuli with a complex spectrum of activities ranging from acute defense mechanisms to cell differentiation or cytokine release. However, the individual intracellular signaling pathways related to these functions are not well understood. CXC chemokine ligand 4 (CXCL4) represents a broad activator of monocytes, which induces acute as well as delayed activities in these cells including cell differentiation, survival, or the release of ROS, and cytokines. Here, we report for the first time that CXCL4-treated monocytes significantly upregulate sphingosine kinase 1 (SphK1) mRNA and that CXCL4 induces SphK1 enzyme activity as well as its translocation to the cell membrane. Furthermore, we could show that pharmacological inhibition of SphK results in reversal of CXCL4-induced monocyte survival, cytokine expression, and release of oxygen radicals, which was confirmed by the use of SphK1-specific siRNA. CXCL4-mediated rescue from apoptosis, which is accompanied by inhibition of caspases, is controlled by SphK1 and its downstream element Erk. Taken together, these data assign SphK1 as a central regulator of acute and delayed monocyte activation and suggest SphK1 as a potential therapeutic target to suppress pro-inflammatory responses induced by CXCL4.Key words: Chemokines . Monocytes . Signal transduction . Sphingosine kinase IntroductionMonocytes are members of the mononuclear phagocyte system and represent one of the most flexible cell types within the immune system. These cells are critically important in the regulation of innate and adaptive immune responses by generation of inflammatory mediators, antigen presentation, phagocytosis, and killing of microorganisms. Monocytes are highly mobile cells and can rapidly accumulate at sites of inflammation. However, a successful defense requires not only the presence of monocytes at inflammatory sites but also fast and effective mechanisms for their activation. In previous reports we described monocyte activation by CXC chemokine ligand 4 (CXCL4; platelet factor 4) [1][2][3]. CXCL4 belongs to the family of CXC-chemokines and is rapidly released in high concentrations upon platelet activation [4,5]. Although no data exist in the literature concerning CXCL4 concentrations at a site of acute platelet activation in vivo, normal serum concentrations of CXCL4 (1-2.5 mM) [6] are sufficient to induce a full monocyte response [1]. Moreover, in regions of acute platelet activation where such platelet-monocyte interaction may take place, concentrations of CXCL4 are likely to be much higher.Although CXCL4 does not induce typical chemokine responses such as chemotaxis or calcium mobilization in monocytes, CXCL4 1162induces ROS formation, increases phagocytosis, and protects these cells from undergoing spontaneous apoptosis [1,2]. Furthermore, CXCL4 treatment provokes monocytes to express and to release several pro-inflammatory cytokines and chemokines [1,3], and stimulates the differentiation of these cells into a specific subtype of macrophages la...

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“…However, PF-4 stimulates monocytes to induce apoptosis in endothelial cells [28]. Although PF-4var is also not chemotactic for monocytes, it does stimulate the migration of immature dendritic cells, activated T cells and NK cells [13].…”

Section: Discussionmentioning

confidence: 99%

PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function

Sutter

Veire

Struyf

et al. 2013

European Heart Journal

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Background: Platelet-derived chemokines are implicated in several aspects of vascular biology. However, for the chemokine platelet factor 4 variant (PF-4var/CXCL4L1), released by platelets during thrombosis and with different properties as compared to PF-4/CXCL4, its role in heart disease is not yet studied. We evaluated the determinants and prognostic value of the platelet-derived chemokines PF-4var, PF-4 and RANTES/CCL5 in patients with stable coronary artery disease (CAD).

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Platelet factor 4/CXCL4-stimulated human monocytes induce apoptosis in endothelial cells by the release of oxygen radicals

Cited by 48 publications

References 49 publications

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

CXCL4‐induced monocyte survival, cytokine expression, and oxygen radical formation is regulated by sphingosine kinase 1

PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function

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