Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β through the JAK2/STAT3 and ERK signaling pathways.

We previously reported that interleukin (IL)-6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor-α (TNF-α) and IL-1β in RN IL-6-mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL-6 three weeks after SNI, increased protein levels of both TNF-α and IL-1β were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF-α and IL-1β were closely correlative with IL-6 and suppressed by intrarubral injection of a neutralizing antibody against IL-6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up-regulations of local TNF-α and IL-1β. Further experiments indicated that intrarubral injection of exogenous IL-6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF-α and IL-1β. Pretreatment with AG490 could block IL-6-induced tactile hypersensitivity and suppress the up-regulations of both TNF-α and IL-1β. However, injection of PD98059 in advance only inhibited the upregulation of IL-1β, but not TNF-α. These findings indicate that RN IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β. IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway, and the production of IL-1β through the JAK2/STAT3 and ERK pathways.

Yang QQ ，Li HN ，Zhang ST ，Yu YL ，Wei W ，Zhang X ，Wang JY ，Zeng XY ... -  《-》

Red nucleus interleukin-6 participates in the maintenance of neuropathic pain through JAK/STAT3 and ERK signaling pathways.

We previously reported that interleukin-6 (IL-6) in the red nucleus (RN) is up-regulated at 3weeks after spared nerve injury (SNI), and plays facilitated role in the later maintenance of neuropathic pain. The current study aimed to reveal the roles of different signaling pathways, including Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT), in RN IL-6-mediated pain modulation. In accord with the increase of IL-6 in the RN following SNI, the protein levels of phospho-STAT3 (p-STAT3), p-ERK and p-JNK were also up-regulated in the RN contralateral to the nerve injury side at 3weeks after SNI. The increases of p-STAT3 and p-ERK (but not p-JNK) were associated with IL-6 and could be blocked by anti-IL-6 antibody. Microinjection of JAK2 inhibitor AG490, ERK inhibitor PD98059 and also JNK inhibitor SP600125 into the RN significantly increased the paw withdrawal threshold (PWT) and alleviated SNI-induced mechanical allodynia. Further studies showed that microinjection of recombinant rat IL-6 (rrIL-6, 20ng) into the RN of normal rats significantly decreased the PWT of rats and increased the local protein levels of p-STAT3 and p-ERK, but not p-JNK. Pre-treatment with AG490 and PD98059 could prevent IL-6-induced mechanical allodynia. Whereas, p-p38 MAPK and p-AKT did not show any expression changes in the RN of rats with SNI or rats treated with rrIL-6. These results suggest that RN IL-6 participates in the later maintenance of SNI-induced neuropathic pain and plays facilitated role through activating JAK/STAT3 and ERK signaling pathways.

Ding CP ，Guo YJ ，Li HN ，Wang JY ，Zeng XY ... -  《-》

Red nucleus interleukin-1β evokes tactile allodynia through activation of JAK/STAT3 and JNK signaling pathways.

We previously reported that interleukin-1β (IL-1β) in the red nucleus (RN) is involved in pain modulation and exerts a facilitatory effect in the development of neuropathic pain. Here, we explored the actions of signaling pathways, including the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-κB (NF-κB) pathways, on RN IL-1β-mediated pain modulation. After a single dose of recombinant rat IL-1β (rrIL-1β, 10 ng) injected into the RN in normal rats, a tactile allodynia was evoked in the contralateral but not ipsilateral hindpaw, commencing 75 min and peaking 120 min postinjection. Up-regulated protein levels of phospho-STAT3 (p-STAT3) and p-JNK were observed in the RN 120 min after rrIL-1β injection, the increases of p-STAT3 and p-JNK were blocked by anti-IL-1β antibody. However, the expression levels of p-ERK, p-p38 MAPK, and NF-κB in the RN were not affected by rrIL-1β injection. RN neurons and astrocytes contributed to IL-1β-evoked up-regulation of p-STAT3 and p-JNK. Further studies demonstrated that injection of the JAK2 antagonist AG490 or JNK antagonist SP600125 into the RN 30 min prior to the administration of rrIL-1β could completely prevent IL-1β-evoked tactile allodynia, while injection of the ERK antagonist PD98059, p38 MAPK antagonist SB203580, or NF-κB antagonist PDTC did not affect IL-1β-evoked tactile allodynia. In conclusion, our data provide additional evidence that RN IL-1β is involved in pain modulation, and that it exerts a facilitatory effect by activating the JAK/STAT3 and JNK signaling pathways.

Guo YJ ，Li HN ，Ding CP ，Han SP ，Wang JY ... -  《-》

Red nucleus IL-33 facilitates the early development of mononeuropathic pain in male rats by inducing TNF-α through activating ERK, p38 MAPK, and JAK2/STAT3.

Li HN ，Yang QQ ，Wang WT ，Tian X ，Feng F ，Zhang ST ，Xia YT ，Wang JX ，Zou YW ，Wang JY ，Zeng XY ... -  《Journal of Neuroinflammation》

Electroacupuncture ameliorates mechanical hypersensitivity by down-regulating spinal Janus kinase 2/signal transducer and activation of transcription 3 and interleukin 6 in rats with spared nerve injury.

Wang Y ，Xia YY ，Xue M ，Jiang Q ，Huang Z ，Huang C ... -  《-》