Differential inflammatory activation of IL-6 (-/-) astrocytes.
IL-6 is a major immunomodulatory cytokine with neuroprotective activity. The absence of interleukin-6 (IL-6) results in increased vulnerability of dopaminergic neurons to the neurotoxicant, MPTP, and a compromised reactive microgliosis. To determine how astrogliosis may contribute to nigrostriatal degeneration in IL-6 (-/-) mice, the inflammatory profiles of astrocytes of IL-6 genotype were compared. Fourteen cytokines and four chemokines were simultaneously assayed in the supernatants of LPS-stimulated primary astrocyte cultures. In a time course of 6, 18 and 48 h and LPS stimulations of 0, 0.1, 1, 10 and 100 ng/ml, IL-6 (-/-) astrocytes secreted significantly greater amounts of the pro-inflammatory cytokines IL-1alpha, IL-1beta and TNFalpha than did IL-6 (+/+) cells. Elevated levels of IL-10 and IL-12p40 were only detected at 48 h post-stimulation with greater IL-10 in IL-6 (-/-) supernatants and greater IL-12p40 in IL-6 (+/+) supernatants. IL-6 (+/+) astrocytes produced more G-CSF and GM-CSF when compared with IL-6 (-/-) astrocytes. Chemokine levels were greater in supernatants of IL-6 (+/+) astrocytes than IL-6 (-/-) cells prior to 48 h post-stimulation. At that time, higher levels of MIP-1alpha were maintained in IL-6 (+/+) supernatant, while similar levels of MCP-1 in supernatants of both IL-6 (+/+) and IL-6 (-/-) cells were measured. Additionally, LPS (100 ng/ml) resulted in greater levels of KC and Rantes in IL-6 (-/-) astrocyte supernatants compared with IL-6 (+/+) supernatants at that time. These results suggest that the autocrine modulatory activities of IL-6 affect multiple cytokine secretory pathways, which could participate in neurodegenerative processes.
Bolin
L M
LM
The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089-1605, USA. lbolin@thepi.org
Zhaung
A
A
Strychkarska-Orczyk
I
I
Nelson
E
E
Huang
I
I
Malit
M
M
Nguyen
Q
Q
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D020267:MPTP Poisoning / Q000276:immunology; D008297:Male; D051379:Mice
D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides