Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner
By binding β2-integrins both ICAM-1 and the receptor for advanced glycation end products (RAGE) mediate leukocyte recruitment in a stimulus-dependent manner. Using different inflammatory mouse models we investigated how RAGE and ICAM-1 are involved in anti-inflammatory functions of protein C (PC; Ce...
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| Format: | Article |
| Language: | English |
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Wiley
2014-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2014/743678 |
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| author | Natascha Braach Kirsten Buschmann Johanna Pflaum Hannes Hudalla Lutz Koch Eduard Ryschich Johannes Poeschl David Frommhold |
| author_facet | Natascha Braach Kirsten Buschmann Johanna Pflaum Hannes Hudalla Lutz Koch Eduard Ryschich Johannes Poeschl David Frommhold |
| author_sort | Natascha Braach |
| collection | DOAJ |
| description | By binding β2-integrins both ICAM-1 and the receptor for advanced glycation end products (RAGE) mediate leukocyte recruitment in a stimulus-dependent manner. Using different inflammatory mouse models we investigated how RAGE and ICAM-1 are involved in anti-inflammatory functions of protein C (PC; Ceprotin, 100 U/kg). We found that, depending on the stimulus, RAGE and ICAM-1 are cooperatively involved in PC-induced inhibition of leukocyte recruitment in cremaster models of inflammation. During short-term proinflammatory stimulation (trauma, fMLP, and CXCL1), ICAM-1 is more important for mediation of anti-inflammatory effects of PC, whereas RAGE plays a major role after longer proinflammatory stimulation (TNFα). In contrast to WT and Icam-1−/− mice, PC had no effect on bronchoalveolar neutrophil emigration in RAGE−/− mice during LPS-induced acute lung injury, suggesting that RAGE critically mediates PC effects during acute lung inflammation. In parallel, PC treatment effectively blocked leukocyte recruitment and improved survival of WT mice and Icam-1-deficient mice in LPS-induced endotoxemia, but failed to do so in RAGE-deficient mice. Exploring underlying mechanisms, we found that PC is capable of downregulating intracellular RAGE and extracellular ICAM-1 in endothelial cells. Taken together, our data show that RAGE and ICAM-1 are required for the anti-inflammatory functions of PC. |
| format | Article |
| id | doaj-art-1e5bdb9783f7425284932355060f387c |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-1e5bdb9783f7425284932355060f387c2025-02-03T01:20:42ZengWileyMediators of Inflammation0962-93511466-18612014-01-01201410.1155/2014/743678743678Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent MannerNatascha Braach0Kirsten Buschmann1Johanna Pflaum2Hannes Hudalla3Lutz Koch4Eduard Ryschich5Johannes Poeschl6David Frommhold7Department of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Surgery, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Neonatology, Ruprecht-Karls-University Hospital Heidelberg, 69120 Heidelberg, GermanyBy binding β2-integrins both ICAM-1 and the receptor for advanced glycation end products (RAGE) mediate leukocyte recruitment in a stimulus-dependent manner. Using different inflammatory mouse models we investigated how RAGE and ICAM-1 are involved in anti-inflammatory functions of protein C (PC; Ceprotin, 100 U/kg). We found that, depending on the stimulus, RAGE and ICAM-1 are cooperatively involved in PC-induced inhibition of leukocyte recruitment in cremaster models of inflammation. During short-term proinflammatory stimulation (trauma, fMLP, and CXCL1), ICAM-1 is more important for mediation of anti-inflammatory effects of PC, whereas RAGE plays a major role after longer proinflammatory stimulation (TNFα). In contrast to WT and Icam-1−/− mice, PC had no effect on bronchoalveolar neutrophil emigration in RAGE−/− mice during LPS-induced acute lung injury, suggesting that RAGE critically mediates PC effects during acute lung inflammation. In parallel, PC treatment effectively blocked leukocyte recruitment and improved survival of WT mice and Icam-1-deficient mice in LPS-induced endotoxemia, but failed to do so in RAGE-deficient mice. Exploring underlying mechanisms, we found that PC is capable of downregulating intracellular RAGE and extracellular ICAM-1 in endothelial cells. Taken together, our data show that RAGE and ICAM-1 are required for the anti-inflammatory functions of PC.http://dx.doi.org/10.1155/2014/743678 |
| spellingShingle | Natascha Braach Kirsten Buschmann Johanna Pflaum Hannes Hudalla Lutz Koch Eduard Ryschich Johannes Poeschl David Frommhold Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner Mediators of Inflammation |
| title | Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner |
| title_full | Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner |
| title_fullStr | Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner |
| title_full_unstemmed | Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner |
| title_short | Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner |
| title_sort | anti inflammatory functions of protein c require rage and icam 1 in a stimulus dependent manner |
| url | http://dx.doi.org/10.1155/2014/743678 |
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