Mustafa Shamimunisa B, Hernandez Tania F, Johnson-Pais Teresa L, Kumar Pratap A, Petershack Jean A, Henson Barbara M, Seidner Steven R
Department of Pediatrics/Division of Neonatology, University of Texas Health Science Center, 7703 Floyd Curl Drive, MSC 7812, San Antonio, TX, 78229-3900, USA.
Department of Urology, University of Texas Health Science Center, 7703 Floyd Curl Drive, MSC 7812, San Antonio, TX, 78229-3900, USA.
J Cell Commun Signal. 2020 Sep;14(3):303-314. doi: 10.1007/s12079-019-00533-7. Epub 2019 Oct 29.
Intra-amniotic exposure to proinflammatory cytokines such as interleukin-1 (IL-1) correlates with a decreased incidence of respiratory distress syndrome (RDS) in infants following premature birth. At birth, inadequate absorption of fluid from the fetal lung contributes to the onset RDS. Lung fluid clearance is coupled to Na transport via epithelial sodium channels (ENaC). In this study, we assessed the effects of IL-1 on the expression of ENaC, particularly the α-subunit which is critical for fetal lung fluid clearance at birth. Cultured mouse lung epithelial (MLE-12) cells were treated with either IL-1α or IL-1β to determine their effects on α-ENaC expression. Changes in IL-1-induced α-ENaC levels in the presence of IL-1 receptor antagonist (IL-1ra), cycloheximide, NF-κB inhibitor, and MAP kinase inhibitors were investigated. IL-1α and IL-1β independently induced a significant increase of α-ENaC mRNA and protein after 24 h compared to untreated cells. IL-1-dependent increases in α-ENaC protein were mitigated by IL-1ra and cycloheximide. IL-1 exposure induced NF-κB binding activity. Attenuation of IL-1-induced NF-κB activation by its inhibitor SN50 decreased α-ENaC protein abundance. Inhibition of ERK 1,2 MAPK significantly decreased both IL-1α and β-induced α-ENaC protein expression whereas inhibition of p38 MAPK only blocked IL-1β-induced α-ENaC protein levels. In contrast, IL-1-induced α-ENaC protein levels were unaffected by a c-Jun N-terminal kinase (JNK) inhibitor. Our results suggest that in MLE-12 cells, IL-1-induced elevation of α-ENaC is mediated via NF-κB activation and in part involves stimulation of the ERK 1,2 and p38 MAPK signaling pathways.
羊膜腔内暴露于白细胞介素 -1（IL-1）等促炎细胞因子与早产婴儿呼吸窘迫综合征（RDS）发病率降低相关。出生时，胎儿肺内液体吸收不足会导致RDS的发生。肺液清除与通过上皮钠通道（ENaC）的钠转运相关。在本研究中，我们评估了IL-1对ENaC表达的影响，特别是对出生时胎儿肺液清除至关重要的α亚基。用IL-1α或IL-1β处理培养的小鼠肺上皮（MLE-12）细胞，以确定它们对α-ENaC表达的影响。研究了在存在IL-1受体拮抗剂（IL-1ra）、放线菌酮、NF-κB抑制剂和丝裂原活化蛋白激酶（MAPK）抑制剂的情况下，IL-1诱导的α-ENaC水平的变化。与未处理的细胞相比，IL-1α和IL-1β在24小时后分别独立诱导α-ENaC mRNA和蛋白显著增加。IL-1ra和放线菌酮减轻了IL-1依赖性α-ENaC蛋白的增加。IL-1暴露诱导NF-κB结合活性。其抑制剂SN50对IL-1诱导的NF-κB激活的减弱降低了α-ENaC蛋白丰度。抑制ERK 1,2 MAPK显著降低了IL-1α和β诱导的α-ENaC蛋白表达，而抑制p38 MAPK仅阻断了IL-1β诱导的α-ENaC蛋白水平。相反，IL-1诱导的α-ENaC蛋白水平不受c-Jun N端激酶（JNK）抑制剂的影响。我们的结果表明，在MLE-12细胞中，IL-1诱导的α-ENaC升高是通过NF-κB激活介导的，并且部分涉及ERK 1,2和p38 MAPK信号通路的刺激。
