IL-10 and glucocorticoids inhibit Abeta(1-42)- and lipopolysaccharide-induced pro-inflammatory cytokine and chemokine induction in the central nervous system.
Alzheimer's disease (AD) is characterized by neuropil threads composed of structurally abnormal neurites, neurons containing paired helical filaments of tau protein, and extracellular deposits of amyloid-beta (Abeta) peptide, a protein fragment having neurotoxic and glial immune response activating potential. In the present study, we demonstrate that an acute intracerebroventricular (icv) injection of Abeta(1-42) in the mouse induces a time- and dose-dependent production of IL-1alpha, IL-1beta, IL-6 and MCP-1 in the hippocampus and cortex as measured by ELISA. Cytokine and chemokine levels were maximal at 9 h, with MCP-1 and IL-1alpha remaining elevated over a 24 h period and IL-1beta remaining elevated over a 48 h period. The temporal profile of Abeta-induced cytokine induction differed from that observed for LPS. Following an icv injection of LPS, maximal levels of IL-1alpha, IL-1beta, IL-6 and MCP-1 were attained by 9 h and, except for MCP-1, returned to levels indistinguishable from control at 24 h. MCP-1 remained elevated at 24 h and returned to basal levels at 48 h. In contrast, little production of TNF-alpha was observed under either Abeta or LPS acute stimulus conditions. Treatment with anti-inflammatory agents such as prednisolone, dexamethasone, or IL-10 inhibited both Abeta- and LPS-induced cytokine and chemokine production in the brain. In summary, icv administration of Abeta and LPS induced elevated brain levels of pro-inflammatory cytokines that could be inhibited by immune suppressing drugs and anti-inflammatory proteins, thus providing support for the utility of anti-inflammatory therapeutics in modulating the immunopathology observed in brain inflammatory diseases such as AD.
CNS Department, Aventis Pharmaceuticals, Inc Bridgewater, New Jersey 08807-0800, USA.
Ann Marie
AM
Szczepanik
Garth E
GE
Ringheim
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex; D018925:Chemokines / Q000032:analysis / Q000096:biosynthesis*; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus; D007249:Inflammation; D007276:Injections, Intraventricular; D016753:Interleukin-10 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016753:Interleukin-10