Fast modulation of heat-activated ionic current by proinflammatory interleukin 6 in rat sensory neurons.
The pro-inflammatory cytokine interleukin-6 (IL-6) together with its soluble receptor (sIL-6R) induces and maintains thermal hyperalgesia. It facilitates the heat-induced release of calcitonin gene-related peptide from rat cutaneous nociceptors in vivo and in vitro. Here we report that exposure of nociceptive neurons to the IL-6-sIL-6R complex or the gp130-stimulating designer IL-6-sIL-6R fusion protein Hyper-IL-6 (HIL-6) resulted in a potentiation of heat-activated inward currents (I(heat)) and a shift of activation thresholds towards lower temperatures without affecting intracellular calcium levels. The Janus tyrosine kinase inhibitor AG490, the selective protein kinase C (PKC) inhibitor, bisindolylmaleimide 1 (BIM1), as well as rottlerin, a selective blocker of the PKCdelta isoform, but not the cyclooxygenase inhibitor indomethacin, effectively reduced the effect. Reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization revealed expression of mRNA for the signal-transducing beta subunit of the receptor gp130 in neuronal somata, rather than satellite cells in rat dorsal root ganglia. Together, the results suggest that IL-6-sIL-6R acts directly on sensory neurons. It increases their susceptibility to noxious heat via the gp130/Jak/PKCdelta signalling pathway.
Obreja
O
O
Institut für Physiologie und Experimentelle Pathophysiologie, Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany.
Biasio
W
W
Andratsch
M
M
Lips
K S
KS
Rathee
P K
PK
Ludwig
A
A
Rose-John
S
S
Kress
M
M
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D006358:Hot Temperature / Q000009:adverse effects*; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology*; D053613:Janus Kinase 1; D008301:Maleimides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051745:Protein Kinase C-delta; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012684:Sensory Thresholds / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D000098:Acetophenones; D015703:Antigens, CD; D001578:Benzopyrans; D016861:Cyclooxygenase Inhibitors; C494201:Il6st protein, rat; D007211:Indoles; D015850:Interleukin-6; D008301:Maleimides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D050822:Cytokine Receptor gp130; C085746:rottlerin; C497260:Prkcd protein, rat; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C088060:bisindolylmaleimide; D002118:Calcium; D007213:Indomethacin