Selective increases in cytokine expression in the rat brain in response to striatal injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and interleukin-1.
A number of cytokines contribute to acute experimental neurodegeneration. The cytokine response can have detrimental or beneficial effects depending on the temporal profile and balance between pro- and anti-inflammatory molecules. Our recent data suggest that the pro-inflammatory cytokine interleukin-1beta (IL-1beta) acts at specific sites (e.g., the striatum) in the rat brain to cause distant cortical injury, when co-administered with the potent excitotoxin alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA). The objective of the present study was to investigate changes in the expression of several cytokines simultaneously in the rat striatum and cortex after intrastriatal administration of vehicle, S-AMPA or human recombinant (hr) IL-1beta alone or S-AMPA co-injected with hrIL-1beta using reverse transcription-polymerase chain reaction (RT-PCR; Taqman fluorogenic probes) and enzyme-linked immunosorbent assay (ELISA). Injection of S-AMPA alone increased IL-6 mRNA expression in the ipsilateral striatum after 8 h, whilst striatal injection of IL-1beta alone increased local IL-1beta and IL-1ra mRNAs. The levels of mRNA encoding IL-1alpha, IL-1beta, IL-1ra, IL-6, IL-10 and TNFalpha were markedly elevated in the ipsilateral cortex 8 h after co-injection of S-AMPA and hrIL-1beta. Cortical mRNA levels for IL-4, IL-18, TGFbeta and IFNgamma were not significantly different between treatment groups after 2 h or 8 h. A similar pattern of change in the levels of IL-1alpha and IL-6 protein was observed 8 h after treatment. These data demonstrate selective increases in the expression of cytokines in areas of remote cell death in response to administration of hrIL-1beta and S-AMPA. Such cytokines may be involved in the ensuing damage, and further clarification of their actions could aid future therapeutic strategies for several acute neurodegenerative disorders.
Allan
S M
SM
School of Biological Sciences, University of Manchester, 1.124 Stopford Building, Oxford Road, M13 9PT, Manchester, UK. stuart.allan@man.ac.uk
Harrison
D C
DC
Read
S
S
Collins
B
B
Parsons
A A
AA
Philpott
K
K
Rothwell
N J
NJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology* / Q000633:toxicity
D016207:Cytokines; D018076:DNA, Complementary; D018690:Excitatory Amino Acid Agonists; D007375:Interleukin-1; D007378:Interleukins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid