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IL-8 Production Cytokine Regulation of Human Microglial Cell

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IL-8 Production Cytokine Regulation of Human Microglial Cell Cytokine Regulation of Human Microglial Cell IL-8 Production Laura C. Ehrlich, Shuxian Hu, Wen S. Sheng, Richard L. Sutton, Gaylan L. Rockswold, Phillip K. Peterson and Chun C. Chao This information is current as of October 1, 2021. J Immunol 1998; 160:1944-1948; ; http://www.jimmunol.org/content/160/4/1944 References This article cites 43 articles, 12 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/160/4/1944.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 1, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cytokine Regulation of Human Microglial Cell IL-8 Production1 Laura C. Ehrlich,* Shuxian Hu,*‡ Wen S. Sheng,* Richard L. Sutton,†‡ Gaylan L. Rockswold,†‡ Phillip K. Peterson,*‡ and Chun C. Chao2*‡ IL-8 involvement in neutrophil activation and chemotaxis may be important in inflammatory responses within the central nervous system, secondary to meningitis, encephalitis, and traumatic injury. The source of IL-8 within the brain during these inflammatory processes, however, is unknown. To explore the role of microglia in the production of IL-8, human fetal microglia, which are the resident macrophages of the brain, were treated with LPS and pro- and anti-inflammatory cytokines to determine their effects on IL-8 production. We found that IL-8 protein levels increased in response to LPS or IL-1b, or to TNF-a, which also corresponded to elevated IL-8 mRNA levels by RT-PCR. Pretreatment with IL-4, IL-10, or TGF-b1 potently inhibited the stimulatory effects of these proinflammatory agents. These findings indicate that human microglia synthesize IL-8 in response to proinflammatory Downloaded from stimuli, and that anti-inflammatory cytokines down-regulate the production of this chemokine. These results may have important therapeutic implications for certain central nervous system insults involving inflammation. The Journal of Immunology, 1998, 160: 1944–1948. cute bacterial (purulent) meningitis occurs when bacteria IL-8, a member of the C-X-C (a) chemokine family, has been gain access to the subarachnoid space, usually via the detected in the cerebrospinal fluid (CSF) of patients with bacterial http://www.jimmunol.org/ A nasopharynx or systemic circulation, prompting the en- meningitis (22–27). Although the role of IL-8 and the specific cells try of neutrophils. Although effective antibiotics are available, sub- that produce it during meningeal inflammation are unknown, stud- stantial mortality due to bacterial meningitis persists and high rates ies have shown that IL-8 is a potent chemoattractant and activator of neurologic sequelae occur in patients who survive the initial of neutrophils (21, 28). This activation may be exhibited by in- infection (1). Recent advances have shown that the inflammatory creased respiratory burst activity, the production of bioactive lip- response in the brain, triggered by bacterial products such as LPS, ids, and the release of lysosomal enzymes, potentially contributing a major cell wall component of Neisseria meningitidis (meningo- to tissue injury (29, 30). IL-8 also regulates neutrophil adhesion to coccus) and Haemophilus influenzae type b (Hib), may be partially endothelial cells (31), possibly mediating the large influx of these responsible for the morbidity (2). cells into the subarachnoid space that is seen in patients with bac- by guest on October 1, 2021 Bacteria induce the production of cytokines by many cell types terial meningitis (2). The release of IL-8 by cells comprising the including leukocytes and endothelial cells (3) that form the vas- BBB (specifically, astrocytes and microglia) may be a key com- cular component of the blood-brain barrier (BBB).3 Additionally, ponent in this influx. astrocytes, which are the predominant cell type on the brain side of Aloisi et al. reported that human astrocytes synthesize IL-8 in the BBB, and microglial cells (contributing up to 20% of the brain response to IL-1b and TNF-a (32), but the production of IL-8 by cells of the BBB (4)) produce a wide variety of cytokines and primary human microglia, which migrate to and proliferate at sites b-chemokines (5–7) when activated. Cytokines appear to either of inflammation (33), has not been shown previously. Therefore, play a protective role or initiate an irreversible over-reaction of the we examined IL-8 production by microglia obtained from fetal and immune system ultimately leading to cell death (8). Both IL-1b adult human brain tissue in response to LPS, IL-1b, and TNF-a. and TNF-a are produced during meningeal inflammation (9–13) We also investigated the regulatory effects of anti-inflammatory and have been implicated in cellular damage (14–18). Further- cytokines (IL-4, IL-10, and TGF-b) on IL-8 production by micro- more, they have been found to initiate an inflammatory cascade glial cells, since the regulation of IL-8 seems critical to the control (19) that includes the release of IL-8 (20, 21). of the inflammatory response in conditions such as meningitis. Finally, we tested whether LPS or proinflammatory cytokines could induce astrocytes to produce IL-8. *Neuroimmunobiology and Host Defense Laboratory, and †Neurotrauma Research Laboratory, Minneapolis Medical Research Foundation, and ‡University of Minne- sota Medical School, Minneapolis, MN 55404 Materials and Methods Received for publication June 26, 1997. Accepted for publication October 31, 1997. Reagents The costs of publication of this article were defrayed in part by the payment of page TNF-a, IL-1b, IL-4, IL-8, IL-10, TGF-b1, and anti-IL-8 Abs were kindly charges. This article must therefore be hereby marked advertisement in accordance provided by R&D Systems, Inc. (Minneapolis, MN). Anti-goat horseradish with 18 U.S.C. Section 1734 solely to indicate this fact. peroxidase conjugate was obtained from Jackson ImmunoResearch (West 1 This study was financed in part by United States Public Health Service Grants Grove, PA). LPS and Tween-20 were acquired from Sigma Chemical Co. DA-09924 and DA-04381 and a grant from the Alzheimer’s Association. (St. Louis, MO). 2 Address correspondence and reprint requests to Dr. Chun C. Chao, Minneapolis Medical Research Foundation, 914 South 8th St., D-3, Minneapolis, MN 55404. E- Brain cell cultures mail address: [email protected] 3 Abbreviations used in this paper: BBB, blood-brain barrier; CNS, central nervous Human fetal brain tissues were obtained from 16- to 22-wk-old aborted system; MDM, monocyte-derived macrophage; CSF, cerebrospinal fluid; GADPH, fetuses under a protocol approved by the Human Subjects Research Com- glyceraldehyde-3-phosphate dehydrogenase; MIP, macrophage inflammatory protein; mittee at our institution. These cultures were prepared using a previously MCP-1, monocyte chemoattractant protein-1. described technique (34). Briefly, brain tissues were dissociated after a Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 1945 45-min trypsinization (0.125%) and were seeded into 75-cm2 Falcon cul- ture flasks (Fisher Scientific, Pittsburgh, PA) in DMEM (Sigma) containing 10% heat-inactivated serum (Hyclone Laboratories, Logan, UT) and pen- icillin/streptomycin (Sigma). On day 10 to 12 of culture, harvested cells (microglia) were seeded into 96-well plates. Adult brain specimen tissues (;0.01 g) were obtained from patients (with informed consent) undergoing elective or emergency neurosurgical procedures at Hennepin County Medical Center (Minneapolis, MN) and prepared following a slightly modified protocol from that used for pro- cessing fetal microglia. Following trypsinization, cells were resuspended in 35.6 ml PBS, layered over a gradient containing 9.6 ml of 100% Percoll (Sigma) and 4.8 ml of 1.25 M sucrose (Sigma), and centrifuged at 14,000 rpm for 45 min. Collected cells were washed and plated into 75-cm2 flasks. On day 14 of culture, microglia (5 3 103 cells/well) were seeded into 96-well plates. Purified fetal or adult microglia were composed of cell populations, .99% of which stained with CD68 Abs (Dako, Carpenteria, CA), a microglial cell marker, and ,1% of which stained with Abs to glial fibrillary acid protein (Dako), an astrocyte marker. Fetal astrocytes were prepared as previously described (35). More than 99% of the cells were positive for glial fibrillary acid protein. Astrocytes were seeded into 96-well plates at a density of 5 3 103 cells/well. FIGURE 1. Dose-response effects of LPS, IL-1b, and TNF-a on human Monocyte-derived macrophage (MDM) cultures fetal microglial cell IL-8 production. Microglial cells were treated with the Downloaded from Whole blood was drawn from healthy laboratory donors and diluted with indicated concentrations of proinflammatory mediators for 16 h, and su- sterile PBS. This mixture was added to a Ficoll-Hypaque gradient (Lym- pernatants were collected and assayed for IL-8. Data (mean 6 SEM) are phocyte Separation Medium, Organon Teknika Corp., Durham, NC) and representative of three separate experiments with microglia from different centrifuged at 1400 rpm for 30 min. PBMC were collected from the gra- brain tissue specimens. dient and washed three times in PBS.
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