Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation.
Mounting evidence supports the hypothesis that pro-inflammatory cytokines secreted by astrocytes and microglia modulate nociceptive function in the injured CNS and following peripheral nerve damage. Here we examine the involvement of interleukin-1beta (IL-1beta) and microglia activation in nociceptive processing in rat models of spinal cord inflammation. Following application of lipopolysaccharide (LPS) to an ex vivo dorsal horn slice preparation, we observed rapid secretion of IL-1beta which was prevented by inhibition of glial cell metabolism and by inhibitors of either p38 mitogen-activated protein kinase (MAPK) or caspase 1. LPS superfusion also induced rapid secretion of active caspase 1 and apoptosis-associated speck-like protein containing a caspase recruitment domain from the isolated dorsal horn. Extensive microglial cell activation in the dorsal horn, as determined by immunoreactivity for phosphorylated p38 MAPK, was found to correlate with the occurrence of IL-1beta secretion. In behavioural studies, intrathecal injection of LPS in the lumbar spinal cord produced mechanical hyperalgesia in the rat hind-paws which was attenuated by concomitant injections of a p38 MAPK inhibitor, a caspase 1 inhibitor or the rat recombinant interleukin 1 receptor antagonist. These data suggest a critical role for the cytokine IL-1beta and caspase 1 rapidly released by activated microglia in enhancing nociceptive transmission in spinal cord inflammation.
Clark
Anna K
AK
Neurorestoration group, Wolfson Centre for Age Related Disease, Kings College London, London, UK.
D'Aquisto
Fulvio
F
Gentry
Clive
C
Marchand
Fabien
F
McMahon
Stephen B
SB
Malcangio
Marzia
M
D026962:Amino Acid Transport System ASC / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis; D020170:Caspase 1 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000523:psychology; D007278:Injections, Spinal; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism*; D008070:Lipopolysaccharides; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D026962:Amino Acid Transport System ASC; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D048051:p38 Mitogen-Activated Protein Kinases; D020170:Caspase 1; D015740:Calcitonin Gene-Related Peptide