Proinflammatory cytokines, IL-1β and TNF-α, induce expression of interleukin-34 mRNA via JNK- and p44/42 MAPK-NF-κB pathway but not p38 pathway in osteoblasts
Proinflammatory cytokines, IL-1β and TNF-α, induce expression of interleukin-34 mRNA via JNK- and p44/42 MAPK-NF-κB pathway but not p38 pathway in osteoblasts
复制标题
DOI：
10.1007/s00296-010-1688-7
复制
发表时间：
2011-11-01
影响因子：
4
通讯作者：
Monahan, Joseph B.
中科院分区：
文献类型：
--
作者：
Eda, Hiroyuki;Shimada, Hideaki;Monahan, Joseph B.
本研究旨在探讨炎症细胞因子对白细胞介素 - 34（IL - 34）和巨噬细胞集落刺激因子（M - CSF）mRNA的诱导作用，以及丝裂原活化蛋白激酶（MAPKs）在人成骨细胞这一信号通路中的作用，因为IL - 34和M - CSF都与相同的受体c - FMS结合。在四种炎症细胞因子[白细胞介素 - 1β、白细胞介素 - 6、白细胞介素 - 17和肿瘤坏死因子 - α（TNF - α）]中，白细胞介素 - 1β（17倍）和TNF - α（74倍）显著诱导IL - 34 mRNA的表达水平。白细胞介素 - 1β和TNF - α激活成骨细胞内的丝裂原活化蛋白激酶（MAPKs）：p44/42 MAPK、p38和c - Jun N - 末端激酶（JNK）以及核因子 - κB（NF - κB）。JNK抑制剂可降低白细胞介素 - 1β和TNF - α介导的IL - 34 mRNA表达的诱导作用。有趣的是，尽管MEK - 1/2抑制剂处理对细胞因子诱导的IL - 34 mRNA表达增加没有降低作用，但与单独使用每种抑制剂相比，MEK - 1/2抑制剂和JNK抑制剂联合使用显著抑制白细胞介素 - 1β和TNF - α介导的IL - 34 mRNA表达水平。另一方面，白细胞介素 - 1β和TNF - α分别显著诱导M - CSF mRNA表达水平高达7倍和11倍。白细胞介素 - 1β和TNF - α介导的M - CSF mRNA诱导不受p38、JNK和MEK - 1/2抑制剂的影响。然而，NF - κB抑制剂完全抑制这些细胞因子引起的M - CSF mRNA表达升高。这些结果表明，促炎细胞因子白细胞介素 - 1β和TNF - α通过JNK和p44/42 MAPK而非p38诱导人成骨细胞中IL - 34 mRNA的表达，而p38、JNK和p44/42 MAPK不参与这些细胞因子对M - CSF mRNA表达的诱导。
The aim of this study is to investigate the induction of interleukin-34 (IL-34) and macrophage colony-stimulating factor (M-CSF) mRNA by inflammatory cytokines and the involvement of mitogen-activated protein kinases (MAPKs) in this signaling pathway in human osteoblasts as both IL-34 and M-CSF bind to the same receptor c-FMS. Among four inflammatory cytokines [(IL-1 beta, IL-6, IL-17, and tumor necrosis factor-alpha (TNF-alpha)], IL-34 mRNA expression level was dramatically induced by IL-1 beta (17-fold) and TNF-alpha (74-fold). IL-1 beta and TNF-alpha activated the intracellular mitogen-activated protein kinases (MAPKs): p44/42 MAPK, p38, and c-Jun N-terminal kinase (JNK) as well as nuclear factor-kappa B (NF-kappa B) in osteoblasts. IL-1 beta- and TNF-alpha-mediated induction of IL-34 mRNA expression was decreased by JNK inhibitor. Interestingly, although treatment of MEK-1/2 inhibitor showed no reduction in the increase of IL-34 mRNA expression by cytokines, combination of MEK-1/2 inhibitor and JNK inhibitor significantly inhibited IL-1 beta- and TNF-alpha-mediated IL-34 mRNA expression level compared to those by each inhibitor alone. On the other hand, M-CSF mRNA expression level was significantly induced by both IL-1 beta and TNF-alpha by up to 7- and 11-fold, respectively. IL-1 beta- and TNF-alpha-mediated induction of M-CSF mRNA was not affected by p38, JNK, and MEK-1/2 inhibitors. However, NF-kappa B inhibitor completely inhibited the elevation of M-CSF mRNA expression by these cytokines. These results showed that proinflammatory cytokines, IL-1 beta and TNF-alpha, induced the expression of IL-34 mRNA via JNK and p44/42 MAPK but not p38 in human osteoblasts while p38, JNK, and p44/42 MAPK were not involved in the induction of M-CSF mRNA expression by these cytokines.