Interleukin-4 up-regulates 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in human lung cancer cells.
IL-4, an anti-inflammatory cytokine, was found to stimulate 15-PGDH activity in A549 and other lung cancer cells. Increase in 15-PGDH activity was due to increased transcription and decreased protein turnover of 15-PGDH. MMP-9 was shown to result in decreased levels of 15-PGDH in A549 cells. IL-4 induced down-regulation of MMP-9 mRNA and up-regulation of TIMP-1, an inhibitor of MMP-9. These data suggest that IL-4-induced down-regulation of MMP-9 activity may contribute to up-regulation of 15-PGDH in A549 cells. The role of JAK-STAT6 in IL-4-induced 15-PGDH expression was examined by using inhibitors. Inhibitors of JAKs, kaempferol and JAK inhibitor I, attenuated IL-4-stimulated STAT6 phosphorylation and 15-PGDH activity in a comparable concentration-dependent manner. Furthermore, JAK inhibitor I blocked IL-4-induced down-regulation of MMP-9 mRNA and up-regulation of TIMP-1 but not IL-4-stimulated up-regulation of 15-PGDH mRNA. These results indicate that JAK-STAT6 participated in IL-4-induced up-regulation of 15-PGDH through inhibition of MMP-9-mediated degradation. The roles of other signaling kinases in IL-4-induced 15-PGDH expression were also examined by using various inhibitors. Inhibitors of various MAPKs, PI-3K and PKC attenuated significantly IL-4-stimulated 15-PGDH activity indicating that MAPKs, PI-3K/Akt and PKC pathways participated in IL-4-induced up-regulation of 15-PGDH. Our results indicate that IL-4 up-regulates 15-PGDH by increased gene transcription and decreased protein turnover and the up-regulation can be mediated by JAK-STAT6 as well as MAPKs, PI-3K/Akt and PKC pathways.
Chi
Xiuling
X
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Tai
Hsin-Hsiung
HH
D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000201:enzymology*; D015854:Up-Regulation / Q000187:drug effects*
D015847:Interleukin-4; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase