ERK/Egr-1 signaling pathway is involved in CysLT2 receptor-mediated IL-8 production in HEK293 cells

作者：Lin, Kana; Fang, Sanhua^*; Cai, Beilei; Huang, Xueqin; Zhang, Xiayan; Lu, Yunbi; Zhang, Weiping; Wei, Erqing

来源：European Journal of Cell Biology, 2014, 93(7): 278-288.

DOI：10.1016/j.ejcb.2014.05.001

• Cysteinyl leukotriene receptor 2
• Signal transduction
• Interleukin-8
• Extracellular signal-regulated kinase
• Early growth response-1

The CysLT(2) receptor is involved in myocardial ischemia/reperfusion injury, differentiation of colorectal cancers, bleomycin-induced pulmonary inflammation and fibrosis. However, the signal transduction of cysteinyl leukotriene receptor 2 (CysLT(2)) in inflammatory responses remains to be clarified. In HEK293 cells stably expressing hCysLT(1), hCysLT(2) and rGER17, we determined the signaling pathways for interleukin-8 (IL-8) production after CysLT(2) receptor activation. HEK293 cells were stably transfected with the recombinant plasmids of pcDNA3.1(+)-hysLT(1), pcDNA3.1(+)-hCysLT(2) and pcDNA3.1-rGPR17. Leukotriene C-4 (LTC4) and LTD4 were used as the agonists to induce IL-8 production and the related changes in signal molecules. We found that LTC4 and LTD4 significantly induced IL-8 promoter activation in the HEK293 cells stably expressing hCysLT(2), but not in those expressing hCysLT(1) and rGPR17. In hCysLT(2)-HEK293 cells, LTC4 induced elevation of intracellular calcium, ERK1/2 phosphorylation and Egr-1 expression, and stimulated IL-8 expression and release. These responses were blocked by the selective CysLT(2) receptor antagonist HAMI3379. The ERK1/2 inhibitor U0126 inhibited Egr-1 and IL-8 expression as well as IL-8 release, but the JNK and p38 inhibitors did not have the inhibitory effects. Down-regulation of Egr-1 by RNA interference with its siRNA inhibited the LTC4-induced IL-8 expression and release. In conclusion, these findings indicate the ERK-Egr-1 pathway of Cy5LT(2) receptors mediates IL-8 production induced by the pro-inflammatory mediators LTC4 and LTD4.

• 出版日期2014-7
• 单位浙江大学