Abstract
AimsThe receptor for advanced glycation endproducts, RAGE, is a multiligand receptor and NF-κB activator leading to perpetuation of inflammation. We investigated whether and how RAGE is involved in mediation of anti-inflammatory properties of protein C.Methods and ResultsWe analyzed the effect of protein C on leukocyte adhesion and transmigration in WT- and RAGE-deficient mice using intravital microscopy of cremaster muscle venules during trauma- and TNFα-induced inflammation. Both, protein C (PC, Ceprotin, 100 U/kg) and activated protein C (aPC, 24 µg/kg/h) treatment significantly inhibited leukocyte adhesion in WT mice in these inflammation models. The impaired leukocyte adhesion after trauma-induced inflammation in RAGE knockout mice could not be further reduced by PC and aPC. After TNFα-stimulation, however, aPC but not PC treatment effectively blocked leukocyte adhesion in these mice. Consequently, we asked whether RAGE is involved in PC activation. Since RAGE-deficient mice and endothelial cells showed insufficient PC activation, and since thrombomodulin (TM) and endothelial protein C receptor (EPCR) are reduced on the mRNA and protein level in RAGE deficient endothelial cells, an involvement of RAGE in TM-EPCR-dependent PC activation is likely. Moreover, TNFα-induced activation of MAPK and upregulation of ICAM-1 and VCAM-1 are reduced both in response to aPC treatment and in the absence of RAGE. Thus, there seems to be interplay of the RAGE and the PC pathway in inflammation.ConclusionRAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM.
Highlights
Protein C (PC) is synthesized by the liver, endothelial cells, leukocytes, and keratinocytes [1]
Activation of protease-activated-receptor 1 (PAR-1) inhibits NF-kB translocation which results in a reduced production of proinflammatory cytokines and expression of cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [3], and thereby blocks leukocyte recruitment, while signalling mechanism may differ in other cell types [4,5]
The capacity of PC and activated protein C (aPC) to inhibit leukocyte recruitment in wild type (WT) mice was observed by intravital microscopy of leukocyte adhesion in postcapillary venules of inflamed cremaster muscles in two established models
Summary
Protein C (PC) is synthesized by the liver, endothelial cells, leukocytes, and keratinocytes [1]. Binding of thrombin to thrombomodulin (TM) leads to activation of PC, amplified by the endothelial protein C receptor (EPCR) [2]. The aPC-TMEPCR-complex activates protease-activated-receptor 1 (PAR-1) so that activated protein C (aPC) elicits potent anti-inflammatory and cytoprotective effects independent of aPC’s anti-coagulatory properties [1,2]. Activation of PAR-1 inhibits NF-kB translocation which results in a reduced production of proinflammatory cytokines and expression of cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [3], and thereby blocks leukocyte recruitment, while signalling mechanism may differ in other cell types [4,5]. Capture of free flowing leukocytes is followed by leukocyte rolling along the endothelial layer, triggering the activation of the b2-
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