title: Protease-activated receptor-1 protects rat astrocytes from apoptotic cell death via JNK-mediated release of the chemokine GRO/CINC-1.
abstract: Thrombin at low doses is an endogenous mediator of protection in ischaemic and haemorrhagic models of stroke. However, the mechanism of thrombin-induced protection remains unclear. Recently accumulating evidence has shown that astrocytes play an important role in the brain after injury. We report that thrombin and thrombin receptor agonist peptide (TRag) up-regulated secretion of the chemokine growth-regulated oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) in primary rat astrocytes in a concentration-dependent manner. However, we found no increase of interleukin (IL)-6, IL-1beta and tumour necrosis factor-alpha secretion. Protease-activated receptor 1 (PAR-1)-induced GRO/CINC-1 release was mainly mediated by c-Jun N-terminal kinase (JNK) activation. Extracellular signal-regulated kinase 1/2 might be partially involved, but not p38 mitogen-activated protein kinase. Further studies demonstrated that PAR-1 activation, as well as application of recombinant GRO/CINC-1, protected astrocytes from C(2)-ceramide-induced cell death. Protection occurred with suppression of cytochrome c release from mitochondria. The inhibition of cytochrome c release was largely reduced by the antagonist of chemokine receptor CXCR2, SB-332235. Importantly, a specific JNK inhibitor significantly abolished the protective action of PAR-1. These results demonstrate for the first time that PAR-1 plays an important role in anti-apoptosis in the brain by regulating the release of chemokine GRO/CINC-1, which gives a feedback through its receptor CXCR2 to preserve astrocytes from toxic insults.
authors.affiliation: Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.forename: Rolf
authors.initials: R
authors.lastname: Stricker
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D002518:Ceramides / Q000633:toxicity; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018696:Neuroprotective Agents; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D044463:Receptor, PAR-1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002518:Ceramides; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D007375:Interleukin-1; D015850:Interleukin-6; D018696:Neuroprotective Agents; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin