p38 mitogen-activated protein kinase targets the production of proinflammatory endothelial microparticles.
J Thromb Haemost
; 7(4): 701-9, 2009 Apr.
Article
en En
| MEDLINE
| ID: mdl-19192109
ABSTRACT
BACKGROUND:
Endothelial microparticles (EMPs) are irregularly shaped membrane fragments shed into the circulation in patients with vascular diseases, and may themselves act to enhance the endothelial response to inflammation. On the basis of the importance of p38 mitogen-activated protein kinase (MAPK) in endothelial responses to inflammatory stimuli, we sought to define the role of p38 in EMP generation and function.METHODS:
Microparticle generation from cultures of human aortic endothelial cells (hAECs) treated with tumor necrosis factor-alpha (TNF-alpha) and p38 inhibition was quantified via multiple modalities. The response of target endothelial cells was assessed by treatment of cells with EMPs generated under various conditions.RESULTS:
Inhibition of p38 in hAECs, using pharmacologic agents, resulted in a 50% reduction of TNF-alpha-induced EMPs. Importantly, suppression of microparticles was specific to p38 MAPK pathways. EMPs triggered by TNF-alpha activation induced an approximately four-fold increase in soluble intercellular adhesion molecule-1 (sICAM-1) release from targeted cells. However, inhibition of p38 MAPK in the targeted cell prior to EMP treatment did not alter the sICAM1 response.CONCLUSIONS:
Our findings implicate p38 MAPK signaling as significant and selective in the formation and maturation of EMPs. EMPs elicited a proinflammatory response from targeted hAECs that was dependent on the conditions under which EMPs were generated. However, our results imply a unidirectional model in which p38 MAPK is critical at the source of microparticle formation, but not the target cell response to EMPs. These findings indicate a novel mechanism by which p38 inhibition may offer therapeutic benefit in vivo via direct inhibition of EMP formation.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Mediadores de Inflamación
/
Células Endoteliales
/
Proteínas Quinasas p38 Activadas por Mitógenos
/
Inhibidores de Proteínas Quinasas
/
Micropartículas Derivadas de Células
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Thromb Haemost
Asunto de la revista:
HEMATOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos