Interleukin-1beta induces substance P release from primary afferent neurons through the cyclooxygenase-2 system.
Substance P (SP) is synthesized in the dorsal root ganglion (DRG) and released from primary afferent neurons to convey information regarding noxious stimuli. The effects of the proinflammatory cytokine interleukin-1 (IL-1) beta on the release of SP were investigated using primary cultured rat DRG cells. Recombinant mouse IL-1beta added to the cells at 0.1 ng/ml increased the SP-like immunoreactivity (SPLI) in the culture medium after incubation for 6 h by approximately 50% as compared with that of nontreated DRG cells. The effect of IL-1beta was Ca(2+)-dependent and significantly inhibited by 100 ng/ml IL-1 receptor-specific antagonist (IL-1r antagonist), cyclooxygenase (COX) inhibitors such as 0.1 mM aspirin, 1 microg/ml indomethacin, and 1 microM NS-398 (specific for COX-2), and 1 microM dexamethasone. Furthermore, a 1-h incubation with IL-1beta markedly increased the inducible COX-2 mRNA level, which was inhibited by an IL-1r antagonist and dexamethasone, whereas IL-1beta showed no effect on the level of constitutive COX-1 mRNA. These observations indicated that IL-1beta induced the release of SP from the DRG cells via specific IL-1 receptors, the mechanism of which might involve prostanoid systems produced by COX-2. This could be responsible for the hyperalgesic action with reference to inflammatory pain in the primary afferent neuron to spinal cord pathway.
Inoue
A
A
Department of Pharmacology, Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Japan.
Ikoma
K
K
Morioka
N
N
Kumagai
K
K
Hashimoto
T
T
Hide
I
I
Nakata
Y
Y
D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism*; D015320:Tachykinins / Q000235:genetics
D017077:Culture Media, Conditioned; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005938:Glucocorticoids; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007527:Isoenzymes; D011498:Protein Precursors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D004533:Egtazic Acid; D003907:Dexamethasone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases