1. Ccl2 and Ccl3 mediate neutrophil recruitment via induction of protein synthesis and generation of lipid mediators.
- Author
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Reichel CA, Rehberg M, Lerchenberger M, Berberich N, Bihari P, Khandoga AG, Zahler S, and Krombach F
- Subjects
- 1-Alkyl-2-acetylglycerophosphocholine Esterase pharmacology, Animals, Benzoquinones pharmacology, Cells, Cultured, Chemokine CCL2 pharmacology, Chemokine CCL3 pharmacology, Chemotaxis, Leukocyte drug effects, Chemotaxis, Leukocyte physiology, Dactinomycin pharmacology, Disease Models, Animal, Indoles pharmacology, Indomethacin pharmacology, Leukotriene B4 pharmacology, Male, Mice, Mice, Inbred BALB C, Neutrophil Infiltration drug effects, Random Allocation, Sensitivity and Specificity, Chemokine CCL2 metabolism, Chemokine CCL3 metabolism, Lipoxygenase Inhibitors pharmacology, Neutrophil Infiltration physiology, Protein Biosynthesis drug effects
- Abstract
Objective: Although the chemokines monocyte chemoattractant protein-1 (Ccl2/JE/MCP-1) and macrophage inflammatory protein-1alpha (Ccl3/MIP-1alpha) have recently been implicated in neutrophil migration, the underlying mechanisms remain largely unclear., Methods and Results: Stimulation of the mouse cremaster muscle with Ccl2/JE/MCP-1 or Ccl3/MIP-1alpha induced a significant increase in numbers of firmly adherent and transmigrated leukocytes (>70% neutrophils) as observed by in vivo microscopy. This increase was significantly attenuated in mice receiving an inhibitor of RNA transcription (actinomycin D) or antagonists of platelet activating factor (PAF; BN 52021) and leukotrienes (MK-886; AA-861). In contrast, leukocyte responses elicited by PAF and leukotriene-B(4) (LTB(4)) themselves were not affected by actinomycin D, BN 52021, MK-886, or AA-861. Conversely, PAF and LTB(4), but not Ccl2/JE/MCP-1 and Ccl3/MIP-1alpha, directly activated neutrophils as indicated by shedding of CD62L and marked upregulation of CD11b. Moreover, Ccl2/JE/MCP-1- and Ccl3/MIP-1alpha-elicited leakage of fluorescein isothiocyanate dextran as well as collagen IV remodeling within the venular basement membrane were completely absent in neutrophil-depleted mice., Conclusions: Ccl2/JE/MCP-1 and Ccl3/MIP-1alpha mediate firm adherence and (subsequent) transmigration of neutrophils via protein synthesis and secondary generation of leukotrienes and PAF, which in turn directly activate neutrophils. Thereby, neutrophils facilitate basement membrane remodeling and promote microvascular leakage.
- Published
- 2009
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