Unconjugated bilirubin activates and damages microglia

Journal of Neuroscience Research - Tập 84 Số 1 - Trang 194-201 - 2006
Ana Gordo1, Ana S. Falcão1, Adelaide Fernandes1, Maria Alexandra Brito1, Rui F. M. Silva1, Dora Brites2
1Centro de Patogénese Molecular – UBMBE, Faculdade de Farmácia, University of Lisbon, Lisbon, Portugal
2Centro de Patogénese Molecular-UBMBE, Faculdade de Farmácia, University of Lisbon, Lisbon, Portugal

Tóm tắt

AbstractMicroglia are the resident immune cells of the brain and are the principal source of cytokines produced during central nervous system inflammation. We have previously shown that increased levels of unconjugated bilirubin (UCB), which can be detrimental to the central nervous system during neonatal life, induce the secretion of inflammatory cytokines and glutamate by astrocytes. Nevertheless, the effect of UCB on microglia has never been investigated. Hence, the main goal of the present study was to evaluate whether UCB leads to microglial activation and to the release of the cytokines tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐6. Additionally, we investigated the effects of UCB on glutamate efflux and cell death. The results showed that UCB induces morphological changes characteristic of activated microglia and the release of high levels of TNF‐α, IL‐1β, and IL‐6 in a concentration‐dependent manner. In addition, UCB triggered extracellular accumulation of glutamate and an increased cell death by apoptosis and necrosis. These results demonstrate, for the first time, that UCB is toxic to microglial cells and point to microglia as an important target of UCB in the central nervous system. Moreover, they suggest that UCB‐induced cytokine production, by mediating cell injury, can further contribute to exacerbate neurototoxicity. Interestingly, microglia cells are much more responsive to UCB than astrocytes. Collectively, these data indicate that microglia may play an important role in the pathogenesis of encephalopathy during severe hyperbilirubinemia. © 2006 Wiley‐Liss, Inc.

Từ khóa


Tài liệu tham khảo

10.1098/rstb.2003.1358

10.1002/glia.1106

10.1006/exnr.1993.1092

10.1152/ajpcell.1992.263.1.C1

10.1006/abbi.2000.2210

10.1023/A:1015563704551

10.1016/j.brainres.2004.07.063

10.1111/j.1651-2227.1990.tb11323.x

10.1203/00006450-200001000-00013

10.1007/BF02815409

10.1016/0165-5728(95)00148-4

10.1056/NEJM200102223440807

10.1046/j.1471-4159.2003.01829.x

10.1097/00001756-199906230-00009

10.1016/j.nbd.2005.03.001

10.1016/j.jneuroim.2004.04.007

10.1111/j.1471-4159.2006.03680.x

10.1523/JNEUROSCI.09-01-00183.1989

10.1016/S0006-8993(03)03037-3

10.1523/JNEUROSCI.13-01-00029.1993

10.1146/annurev.neuro.22.1.219

Gourley GR, 1997, Bilirubin metabolism and kernicterus, Adv Pediatr, 44, 173, 10.1016/S0065-3101(24)00052-5

10.1016/S0095-5108(02)00053-2

10.1002/(SICI)1098-1136(199804)22:4<401::AID-GLIA9>3.0.CO;2-5

10.1002/glia.10150

10.1002/jnr.20562

10.1016/0166-2236(96)10049-7

10.1159/000081969

Lee SC, 1993, Cytokine production by human fetal microglia and astrocytes Differential induction by lipopolysaccharide and IL‐1 beta, J Immunol, 150, 2659, 10.4049/jimmunol.150.7.2659

Li Y, 2003, Interleukin‐1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38‐MAPK pathway, Neuroscience, 23, 1605, 10.1523/JNEUROSCI.23-05-01605.2003

10.1016/j.brainres.2005.06.085

10.1002/jnr.20481

10.1002/jnr.10093

10.1385/NMM:3:2:65

10.1083/jcb.85.3.890

10.1096/fasebj.5.10.2065887

10.1002/(SICI)1097-4547(19971215)50:6<1023::AID-JNR13>3.0.CO;2-5

10.2174/1568006043481284

10.1016/S0304-3940(01)01943-7

10.1016/S0165-5728(02)00011-5

10.1097/00005072-197101000-00008

Ostrow JD, 1994, Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function, J Lipid Res, 35, 1715, 10.1016/S0022-2275(20)39768-6

10.1203/01.PDR.0000103388.01854.91

10.1111/j.1651-2227.1996.tb13949.x

10.1016/0304-3940(94)90755-2

10.1542/peds.99.4.612

10.1002/glia.20191

Piani D, 1994, Involvement of the cystine transport system xc‐ in the macrophage‐induced glutamate‐dependent cytotoxicity to neurons, J Immunol, 152, 3578, 10.4049/jimmunol.152.7.3578

10.1016/0304-3940(91)90559-C

Porter ML, 2002, Hyperbilirubinemia in the term newborn, Am Fam Physician, 65, 599

10.1016/j.brainresrev.2004.06.006

10.1007/BF03401828

10.1172/JCI119808

10.1016/0024-3205(95)00008-T

10.1002/glia.10274

10.1016/j.brainresrev.2004.12.028

10.1159/000206693

10.1038/sj.jp.7211157

10.4049/jimmunol.175.1.155

10.1006/bbrc.1999.1646

10.1016/S0168-8278(01)00015-0

10.1203/00006450-200204000-00022

10.1016/j.toxlet.2005.09.033

10.1002/glia.10154

10.1016/0006-8993(91)91302-H

10.1002/ana.10519

10.1016/0006-8993(92)91588-6

10.1002/glia.1082

10.1016/S0165-5728(99)00187-3

10.1523/JNEUROSCI.19-13-05236.1999

10.1074/jbc.M104628200

10.1016/0165-5728(91)90110-S

Thông tin
Thông tin xuất bản

Journal of Neuroscience Research

Tập 84 Số 1

194-201

Thông tin tác giả