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prenylated quinolinecarboxylic acid compound-18 通过抑制白细胞介素-31 通路来防止感觉神经纤维的生长。

Prenylated quinolinecarboxylic acid compound-18 prevents sensory nerve fiber outgrowth through inhibition of the interleukin-31 pathway.

机构信息

Fukushima Medical University School of Medicine, Fukushima, Japan.

出版信息

PLoS One. 2021 Feb 4;16(2):e0246630. doi: 10.1371/journal.pone.0246630. eCollection 2021.

DOI:10.1371/journal.pone.0246630
PMID:33539470
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7861556/
Abstract

Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.

摘要

白细胞介素-31（IL-31）参与特应性皮炎（AD）中皮肤感觉神经的过度发育，导致严重瘙痒。我们之前报道过，prenylated quinolinecarboxylic acid（PQA）衍生物 PQA-18 是一种免疫抑制剂，可抑制 p21-activated kinase 2（PAK2），并改善 Nc/Nga 小鼠作为 AD 模型的皮肤损伤。在本研究中，我们研究了 PQA-18 对病变皮肤感觉神经的影响。PQA-18 减轻 Nc/Nga 小鼠皮肤中的感觉神经纤维密度。PQA-18 还抑制 IL-31 诱导的背根神经节培养物中感觉神经纤维的生长。信号分析表明，PQA-18 抑制由 IL-31 受体（IL-31R）激活的 PAK2、Janus 激酶 2 和信号转导和转录激活因子 3（STAT3）的磷酸化，从而抑制 Neuro2A 细胞中的神经突生长。PAK2 的基因沉默分析证实了 STAT3 磷酸化和由 IL-31R 激活引发的神经突生长的要求。LC/MS/MS 分析表明，PQA-18 可防止由 IL-31R 激活诱导的 PAK2 激活复合物的形成。这些结果表明，PQA-18 通过抑制 PAK2 活性抑制 IL-31 途径，从而抑制感觉神经生长。PQA-18 可能是开发 AD 瘙痒症新型药物的有价值的先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/524002f321c4/pone.0246630.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/3b791b8fb732/pone.0246630.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/c2a8e027ad07/pone.0246630.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/4a47b1b8b782/pone.0246630.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/0c591e25db51/pone.0246630.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/44613a5c4476/pone.0246630.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/93cbc2c9fee8/pone.0246630.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/ebf3babc4a89/pone.0246630.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/524002f321c4/pone.0246630.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/3b791b8fb732/pone.0246630.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/c2a8e027ad07/pone.0246630.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/4a47b1b8b782/pone.0246630.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/0c591e25db51/pone.0246630.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/44613a5c4476/pone.0246630.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/93cbc2c9fee8/pone.0246630.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/ebf3babc4a89/pone.0246630.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b7c/7861556/524002f321c4/pone.0246630.g008.jpg

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