Abstract
C3a and C5a anaphylatoxins are proinflammatory polypeptides released during complement activation. They exert their biological activities through interaction with two G protein-coupled receptors named C3aR and C5aR, respectively. In the brain, these receptors are expressed on glial cells, and some recent data have suggested that anaphylatoxins could mediate neuroprotection. In this study, we used RT-PCR and ribonuclease protection assays (RPA) to investigate the role of anaphylatoxins on neurotrophin expression by the human glioblastoma cell line T98G and by rat astrocytes. Our data show that for both cell types, anaphylatoxins upregulate expression of NGF mRNA. This response depended on a G protein-coupled pathway since pre-treatment of cells with pertussis toxin (PTX) completely blocked NGF mRNA increases. This effect was anaphylatoxin-specific since pre-incubation with anti-C3a or anti-C5aR antibodies abolished the effects of C3a and C5a, respectively. The regulation of NGF mRNA by anaphylatoxins was not accompanied by translation into protein expression, but there was a significant synergic effect of anaphylatoxins/IL-1b costimulation. Our demonstration of involvement of anaphylatoxins in the NGF release process by astrocytes suggests that C3a and C5a could modulate neuronal survival in the CNS.
Highlights
Injury in the central nervous system (CNS) produces a multi-faceted, complex cascade of events that includes immunological changes such as activation of the complement system and generation of antibodies, release of pro-inflammatory cytokines and chemokines, and production of reactive oxygen species leading to oxidative stress
To further examine the potential roles of C3a and C5a in the CNS, we examined the release of nerve growth factor (NGF) by astrocytes upon stimulation with anaphylatoxins, which may participate to neuroprotection
C3a and C5a anaphylatoxins increase NGF mRNA expression in human glioblastoma cell line T98G In a first approach, we studied NGF mRNA expression in the human glioblastoma cell line T98G
Summary
Injury in the CNS produces a multi-faceted, complex cascade of events that includes immunological changes such as activation of the complement system and generation of antibodies, release of pro-inflammatory cytokines and chemokines, and production of reactive oxygen species leading to oxidative stress. Intrathecal complement activation has been shown to occur in multiple sclerosis, Alzheimer's disease, bacterial meningitis, stroke and other brain diseases [3,4]. Inflammatory reactions in these disorders are associated with expression of pro-inflammatory cytokines, including IL-1β, TNF-α, IL-6, IFN-γ and IL-8. Excess expression of these cytokines can result in the destruction of the body's own cells, neurons
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