title: M-sec regulates polarized secretion of inflammatory endothelial chemokines and facilitates CCL2-mediated lymphocyte transendothelial migration.
abstract: Activation of endothelial cells by IL-1β triggers the expression of multiple inflammatory cytokines and leukocyte-attracting chemokines. The machineries involved in the secretion of these inducible proteins are poorly understood. With the use of genome-wide transcriptional analysis of inflamed human dermal microvascular endothelial cells, we identified several IL-1β-induced candidate regulators of these machineries and chose to focus our study on TNF-α-induced protein 2 (myeloid-secretory). The silencing of myeloid-secretory did not affect the ability of inflamed endothelial cells to support the adhesion and crawling of effector T lymphocytes. However, the ability of these lymphocytes to complete transendothelial migration across myeloid-secretory-silenced human dermal microvascular endothelial cells was inhibited significantly. These observed effects on lymphocyte transendothelial migration were recovered completely when exogenous promigratory chemokine CXCL12 was overlaid on the endothelial barrier. A polarized secretion assay suggested that the silencing of endothelial myeloid-secretory impairs T effector transendothelial migration by reducing the preferential secretion of endothelial-produced CCL2, a key transendothelial migration-promoting chemokine for these lymphocytes, into the basolateral endothelial compartment. Myeloid-secretory silencing also impaired the preferential secretion of other endothelial-produced inflammatory chemokines, as well as cytokines, such as IL-6 and GM-CSF, into the basolateral endothelial compartment. This is the first evidence of a novel inflammation-inducible machinery that regulates polarized secretion of endothelial CCL2 and other inflammatory chemokines and cytokines into basolateral endothelial compartments and facilitates the ability of endothelial CCL2 to promote T cell transendothelial migration.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel;
authors.forename: Sagi
authors.initials: S
authors.lastname: Barzilai
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel;
authors.forename: Ronnie
authors.initials: R
authors.lastname: Blecher-Gonen
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel;
authors.forename: Zohar
authors.initials: Z
authors.lastname: Barnett-Itzhaki
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel; and.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Zauberman
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yaeli
authors.initials: Y
authors.lastname: Lebel-Haziv
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel;
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; ronen.alon@weizmann.ac.il.
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D000199:Actins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D020405:Dermis / Q000166:cytology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D056726:Genetic Association Studies; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology*; D055806:Microvessels / Q000166:cytology; D025941:Protein Interaction Mapping; D014158:Transcription, Genetic / Q000187:drug effects; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D000199:Actins; D018932:Chemokine CCL2; D016207:Cytokines; D053583:Interleukin-1beta; C085839:TNFAIP2 protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: cytokines; endothelial cells; inflammation; leukocyte trafficking