Different microvascular permeability responses elicited by the CXC chemokines MIP-2 and KC during leukocyte recruitment: role of LSP1.
The CXC chemokines keratinocyte-derived chemokine (KC, CXCL1) and macrophage inflammatory protein-2 (MIP-2, CXCL2) activate G-protein coupled receptor CXCR2 and are believed to have similar inflammatory effects in mice. Their specific signaling mechanisms remain elusive. A wide variety of cellular events, mediators and signaling pathways are known to regulate microvascular permeability. Leukocyte-specific protein 1 (LSP1), a Ca2+- and F-actin binding protein, is one of the major downstream substrates of p38 MAPK. LSP1 was previously shown to play a pivotal role in leukocyte transmigration and microvascular permeability. Using intravital microscopy visualizing microvasculature of murine cremaster muscle, we demonstrate that KC and MIP-2 triggered increased leukocyte recruitment which was significantly reduced in LSP1-deficient mice compared to the wild-type control mice. Fluorescence imaging revealed that KC induced more substantial increases of microvascular permeability to FITC-labeled albumin than MIP-2. We found that LSP1 had a more prominent role in microvascular hyperpermeability induced by KC than that triggered by MIP-2. Moreover, Western blotting showed enhanced phosphorylation of p38 MAPK in the cremasteric tissue after stimulation with KC but not with MIP-2 and KC-induced but not MIP-2-induced hyperpermeability was blunted by pharmacological inhibition of p38 MAPK. In conclusion, LSP1 plays an important role in leukocyte recruitment induced by both KC and MIP-2. KC elicits more profoundly increased microvascular permeability than MIP-2. KC is at least partially effective through LSP1 and the phosphorylation of p38 MAPK.
Department of Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Xi
X
Lei
Mokarram
M
Hossain
Syed M
SM
Qadri
Lixin
L
Liu
D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D054360:Chemokine CXCL1 / Q000494:pharmacology / Q000502:physiology*; D054426:Chemokine CXCL2 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins; D055806:Microvessels / Q000187:drug effects / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002135:Calcium-Binding Proteins; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C057701:Lsp1 protein, mouse; D008840:Microfilament Proteins; D048051:p38 Mitogen-Activated Protein Kinases