CD40-CD40 ligand interactions in human microglia induce CXCL8 (interleukin-8) secretion by a mechanism dependent on activation of ERK1/2 and nuclear translocation of nuclear factor-kappaB (NFkappaB) and activator protein-1 (AP-1).
CXCL8 is a CXC chemokine that recruits leukocytes to sites of inflammation. Expression of CXCL8 in the CNS has been demonstrated in neuroinflammatory diseases, including human immunodeficiency virus (HIV-1) encephalitis, but the mechanism of secretion of this chemokine is not fully understood. CD40 is a 50-kDa protein on the surface of microglia, and we have previously shown that it is increased in expression in HIV-1-infected brain tissue as well as by interferon-gamma (IFNgamma) in tissue culture. We examined the expression and regulation of CXCL8 in cultured human fetal microglia after ligation of CD40 with soluble trimeric CD40 ligand (sCD40L) as well as the expression of CXCL8 on microglia in HIV encephalitic brain tissue sections. Treatment of cultured microglia with IFNgamma + sCD40L resulted in significant induction of CXCL8. This expression was mediated by activation of the ERK1/2 MAPK pathway, as demonstrated by ELISA and Western blot using a specific inhibitor (U0126). Gel shift analyses demonstrated that NFkappaB and AP-1, but not C/EBPbeta, mediate microglial CXCL8 production. We also found increased colocalization of CXCL8 with CD68/CD40-positive cells in HIV encephalitic brain tissue compared with HIV-infected nonencephalitic and normal tissue. Thus, CD40-CD40L interactions facilitate chemokine expression, leading to the influx of inflammatory cells into the CNS. These events can lead to the pathology that is associated with neuroinflammatory diseases.
D'Aversa
Teresa G
TG
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Eugenin
Eliseo A
EA
Berman
Joan W
JW
D015526:AIDS Dementia Complex / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D019013:CD40 Antigens / Q000494:pharmacology; D023201:CD40 Ligand / Q000187:drug effects* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology; D002648:Child; D002675:Child, Preschool; D004660:Encephalitis / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005333:Fetus; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D014018:Tissue Distribution; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D019013:CD40 Antigens; D023201:CD40 Ligand; D048049:Extracellular Signal-Regulated MAP Kinases; D007371:Interferon-gamma; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule