Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+ reuptake in human airway smooth muscle
Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+ reuptake in human airway smooth muscle
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DOI：
10.1152/ajplung.00026.2009
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发表时间：
2009-07-01
影响因子：
4.9
通讯作者：
Sieck, Gary C.
中科院分区：
文献类型：
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作者：
Sathish, Venkatachalem;Thompson, Michael A.;Sieck, Gary C.
Sathish V, Thompson MA, Bailey JP, Pabelick CM, Prakash YS, Sieck GC。促炎细胞因子在调节人气道平滑肌肌浆网Ca2+再摄取中的作用。[J] .中华医学会肺科杂志，2009,31(4):326 - 326。首次发表于2009年4月24日；doi: 10.1152 / ajplung.00026.2009。-气道炎症导致气道平滑肌（ASM）细胞内Ca2+ ([Ca2+](i))水平升高。肌浆网Ca2+释放和再摄取是ASM [Ca2+](i)调节的关键组成部分。Ca2+再摄取通过肌内质网Ca2+ atp酶（SERCA）发生，并在许多细胞类型中受到抑制蛋白磷蛋白（PLB）的调节。在人类ASM中，我们测试了炎症增加PLB的假设，从而抑制SERCA功能，并导致维持[Ca2+](i)水平。令人惊讶的是，我们发现人类ASM不表达PLB蛋白（尽管可以检测到mRNA）。一夜暴露于促炎细胞因子TNF α和IL-13中不会诱导PLB表达，这就提出了SERCA是如何调节的问题。然后我们发现直接SERCA磷酸化（通过CaMKII）发生在人类ASM中。在携带fura-2的人ASM细胞中，我们发现CaMKII拮抗剂jk -93显著减缓了ACh或缓激素诱导的[Ca2+](i)瞬态下降的速度（在零细胞外Ca2+），表明CaMKII介导的SERCA调节的作用。细胞因子暴露降低了SERCA的表达，并且暴露于TNF α和IL-13的细胞中[Ca2+](i)瞬态下降的速度减慢。细胞因子对Ca2+再摄取的影响不受额外暴露于KN-93的影响。这些数据表明，在人类ASM中，SERCA受CaMKII等机制的调节，气道炎症通过降低SERCA表达和减缓Ca2+再摄取来维持[Ca2+](i)水平。
Sathish V, Thompson MA, Bailey JP, Pabelick CM, Prakash YS, Sieck GC. Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+ reuptake in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 297: L26-L34, 2009. First published April 24, 2009; doi: 10.1152/ajplung.00026.2009.-Airway inflammation leads to increased intracellular Ca2+ ([Ca2+](i)) levels in airway smooth muscle (ASM) cells. Sarcoplasmic reticulum Ca2+ release and reuptake are key components of ASM [Ca2+](i) regulation. Ca2+ reuptake occurs via sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) and is regulated by the inhibitory protein phospholamban (PLB) in many cell types. In human ASM, we tested the hypothesis that inflammation increases PLB, thus inhibiting SERCA function, and leading to maintained [Ca2+](i) levels. Surprisingly, we found that human ASM does not express PLB protein (although mRNA is detectable). Overnight exposure to the proinflammatory cytokines TNF alpha and IL-13 did not induce PLB expression, raising the issue of how SERCA is regulated. We then found that direct SERCA phosphorylation (via CaMKII) occurs in human ASM. In fura-2-loaded human ASM cells, we found that the CaMKII antagonist KN-93 significantly slowed the rate of fall of [Ca2+](i) transients induced by ACh or bradykinin (in zero extracellular Ca2+), suggesting a role for CaMKII-mediated SERCA regulation. SERCA expression was decreased by cytokine exposure, and the rate of fall of [Ca2+](i) transients was slowed in cells exposed to TNF alpha and IL-13. Cytokine effects on Ca2+ reuptake were unaffected by additional exposure to KN-93. These data indicate that in human ASM, SERCA is regulated by mechanisms such as CaMKII and that airway inflammation maintains [Ca2+](i) levels by decreasing SERCA expression and slowing Ca2+ reuptake.