Rapid chemokine secretion from endothelial cells originates from 2 distinct compartments.

The neutrophil-attracting chemokine interleukin 8 (IL-8) is stored in the Weibel-Palade body (WPB) of endothelial cells (ECs) from which it can be rapidly released after exposure to the secretagogues histamine or thrombin. In this manner, IL-8 may enable rapid recruitment of leukocytes to inflammatory sites. To explore the possible storage of EC-derived chemokines that may attract other subsets of leukocytes, we examined the intracellular localization and secretagogue responsiveness of growth-related oncogene alpha (GROalpha), monocyte chemoattractant protein-1 (MCP-1), eotaxin-3, interferon-gamma-inducible protein 10 (IP-10), and regulated on activation, normal T-cell expressed and secreted (RANTES). While eotaxin-3, GROalpha, and MCP-1 were rapidly released from ECs, the release of the T-cell attractors RANTES and IP-10 was not sensitive to the secretagogues. Moreover, of the 3 former chemokines, only eotaxin-3 was stored in WPBs. GROalpha and MCP-1 resided mainly in smaller vesicles compatible with sorting to a different, histamine-responsive compartment, which has been described in ECs although not reported to contain chemokines. In conclusion, we propose that rapid release of chemokines is restricted to those primarily recruiting leukocytes of the innate immune system, and that their storage in ECs is not restricted to the WPB compartment.

[1]  Alan Morgan,et al.  Secretory granule exocytosis. , 2003, Physiological reviews.

[2]  V. Gerke,et al.  Ca2+ -regulated secretion of tissue-type plasminogen activator and von Willebrand factor in human endothelial cells. , 2002, Biochimica et biophysica acta.

[3]  D. Ogden,et al.  Differential exocytosis from human endothelial cells evoked by high intracellular Ca2+ concentration , 2002, The Journal of physiology.

[4]  P. Meda,et al.  Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo. , 2002, Blood.

[5]  E. Butcher,et al.  Chemokines in rapid leukocyte adhesion triggering and migration. , 2002, Seminars in immunology.

[6]  J. V. van Mourik,et al.  Biogenesis and exocytosis of Weibel-Palade bodies , 2002, Histochemistry and Cell Biology.

[7]  S. Cuvelier,et al.  Shear-dependent Eosinophil Transmigration on Interleukin 4–stimulated Endothelial Cells , 2001, The Journal of experimental medicine.

[8]  Steffen Jung,et al.  Inflammatory Chemokine Transport and Presentation in HEV , 2001, The Journal of experimental medicine.

[9]  R. Breuer,et al.  Eotaxin-3 but not eotaxin gene expression is upregulated in asthmatics 24 hours after allergen challenge. , 2001, American journal of respiratory cell and molecular biology.

[10]  F. Reinholt,et al.  The Ccr7 Ligand ELC (Ccl19) Is Transcytosed in High Endothelial Venules and Mediates T Cell Recruitment , 2001, The Journal of experimental medicine.

[11]  B. Ewenstein,et al.  Regulated Secretion in Endothelial Cells: Biology and Clinical Implications , 2001, Thrombosis and Haemostasis.

[12]  E. Berger,et al.  Localization of α1,3-fucosyltransferase VI in Weibel–Palade bodies of human endothelial cells , 2000 .

[13]  M. Lindsay,et al.  The tetraspanin CD63/lamp3 cycles between endocytic and secretory compartments in human endothelial cells. , 2000, Molecular biology of the cell.

[14]  U. V. von Andrian,et al.  The Cc Chemokine Thymus-Derived Chemotactic Agent 4 (Tca-4, Secondary Lymphoid Tissue Chemokine, 6ckine, Exodus-2) Triggers Lymphocyte Function–Associated Antigen 1–Mediated Arrest of Rolling T Lymphocytes in Peripheral Lymph Node High Endothelial Venules , 2000, The Journal of experimental medicine.

[15]  E. Berger,et al.  Localization of alpha 1,3-fucosyltransferase VI in Weibel-Palade bodies of human endothelial cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  H. Youssoufian,et al.  Targeting of a heterologous protein to a regulated secretion pathway in cultured endothelial cells. , 1999, Blood.

[17]  T. Nishi,et al.  A novel human CC chemokine, eotaxin-3, which is expressed in IL-4-stimulated vascular endothelial cells, exhibits potent activity toward eosinophils. , 1999, Journal of immunology.

[18]  P. Halban,et al.  Storage of tissue-type plasminogen activator in Weibel-Palade bodies of human endothelial cells. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[19]  B. Wolff,et al.  Endothelial Cell “Memory” of Inflammatory Stimulation: Human Venular Endothelial Cells Store Interleukin 8 in Weibel-Palade Bodies , 1998, The Journal of experimental medicine.

[20]  P. Brandtzaeg,et al.  Rapid Secretion of Prestored Interleukin 8 from Weibel-Palade Bodies of Microvascular Endothelial Cells , 1998, The Journal of experimental medicine.

[21]  J. Skepper,et al.  Human endothelial cell storage granules: a novel intracellular site for isoforms of the endothelin-converting enzyme. , 1998, Circulation research.

[22]  J. Skepper,et al.  Evidence using immunoelectron microscopy for regulated and constitutive pathways in the transport and release of endothelin. , 1998, Journal of cardiovascular pharmacology.

[23]  R. Kaufman,et al.  Intracellular trafficking of factor VIII to von Willebrand factor storage granules. , 1998, The Journal of clinical investigation.

[24]  A. Mallet,et al.  IL-4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in helminth infection and atopy. , 1998, Journal of immunology.

[25]  M. Auer,et al.  Transcytosis and Surface Presentation of IL-8 by Venular Endothelial Cells , 1997, Cell.

[26]  J. Emeis,et al.  An Endothelial Storage Granule for Tissue-Type Plasminogen Activator , 1997, The Journal of cell biology.

[27]  C. Mackay,et al.  Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells , 1996, The Journal of cell biology.

[28]  P. Leder,et al.  Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia , 1996, Nature Medicine.

[29]  M. Scully,et al.  Thrombin induces the redistribution and acute release of tissue factor pathway inhibitor from specific granules within human endothelial cells in culture. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[30]  M. Sticherling,et al.  Immunocytochemical localization of the chemokines RANTES and MIP-1 alpha within human platelets and their release during storage. , 1995, International archives of allergy and immunology.

[31]  T. Schall,et al.  Regulation of the production of the RANTES chemokine by endothelial cells. Synergistic induction by IFN-gamma plus TNF-alpha and inhibition by IL-4 and IL-13. , 1995, Journal of immunology.

[32]  E. Kaiserling,et al.  Ultrastructural localization of factor XIIIa , 1994, Journal of cutaneous pathology.

[33]  T. Springer Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[34]  R. Pauwels,et al.  Attenuation of allergic airway inflammation in IL‐4 deficient mice , 1994, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[35]  D. Wagner,et al.  CD63 is a component of Weibel-Palade bodies of human endothelial cells. , 1993, Blood.

[36]  M. Elliott,et al.  Interleukin-8 release and neutrophil degranulation after pediatric cardiopulmonary bypass. , 1993, The Journal of thoracic and cardiovascular surgery.

[37]  A. Mallet,et al.  Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils , 1992, The Journal of experimental medicine.

[38]  E. Butcher Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity , 1991, Cell.

[39]  T. Barbolt,et al.  Histomorphologic Observations for Cynomolgus Monkeys after Subchronic Subcutaneous Injection of Recombinant Human Interleukin-4 , 1991, Toxicologic pathology.

[40]  H. Gralnick,et al.  Gamma-interferon modulates von Willebrand factor release by cultured human endothelial cells. , 1990, Blood.

[41]  A. Sica,et al.  Monocyte chemotactic and activating factor gene expression induced in endothelial cells by IL-1 and tumor necrosis factor. , 1990, Journal of immunology.

[42]  Rodger P. McEver,et al.  Rapid neutrophil adhesion to activated endothelium mediated by GMP-140 , 1990, Nature.

[43]  D. Bainton,et al.  GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. , 1989, The Journal of clinical investigation.

[44]  R. Derynck,et al.  Expression and secretion of gro/MGSA by stimulated human endothelial cells. , 1989, The EMBO journal.

[45]  D. Wagner,et al.  PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells. , 1989, Blood.

[46]  J. Ravetch,et al.  Biochemical characterization of a gamma interferon-inducible cytokine (IP-10) , 1987, The Journal of experimental medicine.

[47]  D. Stern,et al.  Participation of endothelial cells in the protein C-protein S anticoagulant pathway: the synthesis and release of protein S , 1986, The Journal of cell biology.

[48]  M. Shuman,et al.  A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation , 1985, The Journal of cell biology.

[49]  D. Wagner,et al.  Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells , 1982, The Journal of cell biology.

[50]  E. Jaffe,et al.  Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. , 1973, The Journal of clinical investigation.

[51]  E. Weibel,et al.  NEW CYTOPLASMIC COMPONENTS IN ARTERIAL ENDOTHELIA , 1964, The Journal of cell biology.