Regulation of CCL2 and CCL3 Expression in Human Brain Endothelial Cells by Cytokines and Lipopolysaccharide

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2010 Jan 6

PMID 20047691

Citations 75

Authors

Ray Chui

Katerina Dorovini-Zis

Affiliations

Soon will be listed here.

Abstract

Background: Chemokines are emerging as important mediators of CNS inflammation capable of activating leukocyte integrins and directing the migration of leukocyte subsets to sites of antigenic challenge. In this study we investigated the expression, release and binding of CCL2 (MCP-1) and CCL3 (MIP-1alpha) in an in vitro model of the human blood-brain barrier.

Methods: The kinetics of expression and cytokine upregulation and release of the beta-chemokines CCL2 and CCL3 were studied by immunocytochemistry and enzyme-linked immunosorbent assay in primary cultures of human brain microvessel endothelial cells (HBMEC). In addition, the differential binding of these chemokines to the basal and apical endothelial cell surfaces was assessed by immunoelectron microscopy.

Results: Untreated HBMEC synthesize and release low levels of CCL2. CCL3 is minimally expressed, but not released by resting HBMEC. Treatment with TNF-alpha, IL-1beta, LPS and a combination of TNF-alpha and IFN-gamma, but not IFN-gamma alone, significantly upregulated the expression and release of both chemokines in a time-dependent manner. The released CCL2 and CCL3 bound to the apical and basal endothelial surfaces, respectively. This distribution was reversed in cytokine-activated HBMEC resulting in a predominantly basal localization of CCL2 and apical distribution of CCL3.

Conclusions: Since cerebral endothelial cells are the first resident CNS cells to contact circulating leukocytes, expression, release and presentation of CCL2 and CCL3 on cerebral endothelium suggests an important role for these chemokines in regulating the trafficking of inflammatory cells across the BBB in CNS inflammation.

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References

Kennedy K, Strieter R, Kunkel S, Lukacs N, Karpus W . Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1alpha and monocyte chemotactic protein-1. J Neuroimmunol. 1999; 92(1-2):98-108. DOI: 10.1016/s0165-5728(98)00187-8. View

Berman J, Guida M, Warren J, Amat J, Brosnan C . Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. J Immunol. 1996; 156(8):3017-23. View

Cha J, Jeong M, Bae H, Han J, Jeong S, Jin H . Activated platelets induce secretion of interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha and surface expression of intercellular adhesion molecule-1 on cultured endothelial cells. J Korean Med Sci. 2000; 15(3):273-8. PMC: 3054638. DOI: 10.3346/jkms.2000.15.3.273. View

Huang D, Han Y, Rani M, Glabinski A, Trebst C, Sorensen T . Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation. Immunol Rev. 2001; 177:52-67. DOI: 10.1034/j.1600-065x.2000.17709.x. View

Izikson L, Klein R, Charo I, Weiner H, Luster A . Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med. 2000; 192(7):1075-80. PMC: 2193310. DOI: 10.1084/jem.192.7.1075. View

Keane M, Strieter R . The role of CXC chemokines in the regulation of angiogenesis. Chem Immunol. 1999; 72:86-101. DOI: 10.1159/000058728. View

Zach O, Bauer H, Richter K, Webersinke G, Tontsch S, Bauer H . Expression of a chemotactic cytokine (MCP-1) in cerebral capillary endothelial cells in vitro. Endothelium. 1997; 5(3):143-53. DOI: 10.3109/10623329709053394. View

Karpus W, Kennedy K . MIP-1alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphocyte differentiation. J Leukoc Biol. 1997; 62(5):681-7. View

Taskinen H, Roytta M . Increased expression of chemokines (MCP-1, MIP-1alpha, RANTES) after peripheral nerve transection. J Peripher Nerv Syst. 2000; 5(2):75-81. DOI: 10.1046/j.1529-8027.2000.00009.x. View

10.

Harkness K, Sussman J, Davies-Jones G, Greenwood J, Woodroofe M . Cytokine regulation of MCP-1 expression in brain and retinal microvascular endothelial cells. J Neuroimmunol. 2003; 142(1-2):1-9. DOI: 10.1016/s0165-5728(03)00251-0. View

11.

Gerszten R, Garcia-Zepeda E, Lim Y, Yoshida M, Ding H, Gimbrone Jr M . MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999; 398(6729):718-23. DOI: 10.1038/19546. View

12.

Arimilli S, Ferlin W, Solvason N, Deshpande S, Howard M, Mocci S . Chemokines in autoimmune diseases. Immunol Rev. 2001; 177:43-51. DOI: 10.1034/j.1600-065x.2000.17716.x. View

13.

Godiska R, Chantry D, Dietsch G, Gray P . Chemokine expression in murine experimental allergic encephalomyelitis. J Neuroimmunol. 1995; 58(2):167-76. DOI: 10.1016/0165-5728(95)00008-p. View

14.

Cheng L, Wang Q . [Hematopoietic inhibitors elaborated by bone marrow endothelial cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2003; 10(6):485-91. View

15.

Dogan R, Elhofy A, Karpus W . Production of CCL2 by central nervous system cells regulates development of murine experimental autoimmune encephalomyelitis through the recruitment of TNF- and iNOS-expressing macrophages and myeloid dendritic cells. J Immunol. 2008; 180(11):7376-84. DOI: 10.4049/jimmunol.180.11.7376. View

16.

Glabinski A, Tani M, Strieter R, Tuohy V, Ransohoff R . Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am J Pathol. 1997; 150(2):617-30. PMC: 1858292. View

17.

Murphy P . Chemokines and the molecular basis of cancer metastasis. N Engl J Med. 2001; 345(11):833-5. DOI: 10.1056/NEJM200109133451113. View

18.

Glabinski A, Tani M, Tuohy V, Tuthill R, Ransohoff R . Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis. Brain Behav Immun. 1995; 9(4):315-30. DOI: 10.1006/brbi.1995.1030. View

19.

Eugenin E, Osiecki K, Lopez L, Goldstein H, Calderon T, Berman J . CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. J Neurosci. 2006; 26(4):1098-106. PMC: 6674577. DOI: 10.1523/JNEUROSCI.3863-05.2006. View

20.

Hulkower K, Brosnan C, Aquino D, Cammer W, Kulshrestha S, Guida M . Expression of CSF-1, c-fms, and MCP-1 in the central nervous system of rats with experimental allergic encephalomyelitis. J Immunol. 1993; 150(6):2525-33. View