Dexamethasone suppresses interleukin-1β-induced human β-defensin 2 mRNA expression:: involvement of p38 MAPK, JNK, MKP-1, and NF-κB transcriptional factor in A549 cells
Dexamethasone suppresses interleukin-1β-induced human β-defensin 2 mRNA expression:: involvement of p38 MAPK, JNK, MKP-1, and NF-κB transcriptional factor in A549 cells
复制标题
DOI：
10.1111/j.1574-695x.2007.00293.x
复制
发表时间：
2007-10-01
影响因子：
--
通讯作者：
Suh, Seong-Il
中科院分区：
文献类型：
--
作者：
Jang, Byeong-Churl;Lim, Ki-Jo;Suh, Seong-Il
人β-防御素（HBD）-2是一种诱导型抗菌肽，在天然免疫中起重要作用。另一方面，糖皮质激素发挥免疫抑制和抗炎作用。我们以前报道过白细胞介素1 β通过激活核因子-κ B（NF-κ B）转录因子，以及p38丝裂原活化蛋白激酶（MAPK），c-Jun N-末端激酶（JNK）或磷脂酰肌醇-3-激酶/AKT在A549细胞中诱导HBD-2 mRNA表达。本研究进一步探讨地塞米松（dexamethasone，Dex）在转录水平上抑制IL-1 β诱导的A549细胞HBD-2 mRNA表达及其分子机制。有趣的是，Dex减弱了IL-1 β介导的p38 MAPK和JNK的激活，但不减弱AKT的激活。地塞米松增加MAPK磷酸酶（MKP）-1的表达，其通过IL-1 β使p38 MAPK去磷酸化，但不使JNK去磷酸化。然而，尽管Dex不能抑制p65 NF-κ B在IL-1 β作用下的核转位，但它能显著抑制NF-κ B启动子和HBD-2启动子驱动的荧光素酶活性。这些结果表明，Dex通过阻断p65 NF-κ B B的核转录激活以及通过使p38 MAPK和JNK失活来抑制IL-1 β诱导的HBD-2 mRNA表达。具体而言，在A549细胞中，Dex诱导的MKP-1表达负责响应于IL-1 β而使p38 MAPK失活，而不是JNK。
Human beta-defensin (HBD)-2 is an inducible antimicrobial peptide that plays an important role in innate immunity. Glucocorticoids, on the other hand, exert immunosuppressive and anti-inflammatory actions. We have previously reported that interleukin (IL)-1 beta induces HBD-2 mRNA expression through the activation of nuclear factor-kappa B (NF-kappa B) transcriptional factor, as well as p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), or phosphatidylinositol-3-kinase/AKT in A549 cells. In this study, we further investigated whether dexamethasone (Dex) controls IL-1 beta-induced HBD-2 mRNA expression in A549 cells and the molecular mechanism associated with it. Dex suppressed IL-1 beta-induced HBD-2 mRNA expression, which is mediated by a glucocorticoid receptor, at the transcriptional level. Interestingly, Dex attenuated IL-1 beta-mediated activation of p38 MAPK and JNK, but not of AKT. Dex increased the expression of MAPK phosphatase (MKP)-1, which dephosphorylated p38 MAPK, but not JNK, by IL-1 beta. However, although Dex did not inhibit the nuclear translocation of p65 NF-kappa B in response to IL-1 beta, it profoundly inhibited NF-kappa B promoter- and HBD-2 promoter-driven luciferase activities. These results suggest that Dex acts to inhibit IL-1 beta-induced HBD-2 mRNA expression through blockage of the nuclear transcriptional activation of p65 NF-kappa B as well as through inactivation of p38 MAPK and JNK. Specifically, Dex-induced MKP-1 expression is responsible for the inactivation of p38 MAPK, but not JNK, in response to IL-1 beta in A549 cells.