Expression of Chemokines and Their Receptors in Human and Simian Astrocytes: Evidence for a Central Role of TNF and IFN in CXCR4 and CCR5 Modulation JULIANA CROITORU-LAMOURY, 1,2 * GILLES J. GUILLEMIN, 2 FRANC ¸ OIS D. BOUSSIN, 3 BARBARA MOGNETTI, 3 LAURE I. GIGOUT, 1 ARNAUD CHE ´ RET, 1 BRUNO VASLIN, 1 ROGER LE GRAND, 1 BRUCE J. BREW, 2,4 AND DOMINIQUE DORMONT 1 1 Service de Neurovirologie, Commissariat a ` l’Energie Atomique, Fontenay-aux-Roses Cedex, France 2 Centre for Immunology, St. Vincent’s Hospital, University of New South Wales, Sydney, New South Wales, Australia 3 Laboratoire de Radiopathologie, Commissariat a ` l’Energie Atomique, Fontenay-aux-Roses Cedex, France 4 Departments of Neurology and HIV Medicine, St. Vincent’s Hospital, University of New South Wales, Sydney New South Wales, Australia KEY WORDS astrocyte; human; simian; chemokine; receptor; CNS ABSTRACT Chemokines are key mediators of the selective migration of leukocytes that occurs in neurodegenerative diseases and related inflammatory processes. Astrocytes, the most abundant cell type in the CNS, have an active role in brain inflammation. To ascertain the role of astrocytes during neuropathological processes, we have investigated in two models of primary cells (human fetal and simian adult astrocytes) the repertoire of chemo- kines and their receptors expressed in response to inflammatory stimuli. We demonstrated that, in the absence of any stimulation, human fetal and simian adult astrocytes express mRNA for receptors APJ, BOB/GPR15, Bonzo/CXCR6, CCR2, CCR3, CCR5, CCR8, ChemR23, CXCR3/GPR9, CXCR4, GPR1, and V28/CX3CR1. Moreover, TNF and IL-1 significantly increase BOB/GPR15, CCR2, and V28/CX3CR1 mRNA levels in both models. Furthermore, TNF and IFN act synergistically to induce expression of the major core- ceptors for HIV infection, CXCR4 and CCR5, at both the mRNA and protein levels in human and simian astrocytes, whereas CCR3 expression was not affected by cytokine treatment. Finally, TNF/IFN was the most significant cytokine combination in leading to a pro- nounced upregulation in a comparable, time-dependent manner of the production of che- mokines IP-10/CXCL10, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IL-8/CXCL8. In summary, these data suggest that astrocytes serve as an important source of chemokines under the dependence of a complex cytokine regulation, and TNF and IFN are important modulators of chemokines and chemokine receptor expression in human as well as simian astrocytes. Finally, with the conditions we used, there was no difference between species or age of tissue. GLIA 41:354 –370, 2003. © 2003 Wiley-Liss, Inc. Grant sponsor: Agence Nationale de Recherche sur le SIDA, Paris, France; Grant sponsor: Commissariat a ` l’Energie Atomique, Paris, France; Grant spon- sor: National Health and Medical Research Council (NHMRC). *Correspondence to: Dr. Juliana Croitoru-Lamoury, Centre for Immunology, St. Vincent’s Hospital, Victoria Street, Darlinghurst, Sydney 2010, NSW, Aus- tralia. E-mail: j.lamoury@cfi.unsw.edu.au Received 10 June 2002; Accepted 18 September 2002 DOI 10.1002/glia.10181 GLIA 41:354 –370 (2003) © 2003 Wiley-Liss, Inc.