IL-4 regulates COX-2 and PGE2 production in human non-small cell lung cancer.
IL-4 is a type 2 cytokine that may mediate pleiotropic effects in the NSCLC microenvironment. Here, we investigated whether IL-4 regulates PGE(2) production in NSCLC cells. We found that IL-4 inhibited constitutive COX-2 expression and PGE(2) production in A427 and H2122 NSCLC cell lines, and also suppressed IL-1beta-induced COX-2 expression in A549 and RH2 NSCLC cell lines. COX-2 mRNA was decreased in response to IL-4, and promoter analysis indicated that IL-4 inhibited both constitutive and IL-1beta-induced COX-2 transcription. IL-4 inhibited IL-1beta-stimulated ERK phosphorylation, which may mediate the inhibition of IL-1beta-induced COX-2 by IL-4. IL-4 did not modulate additional arachidonic acid pathway enzymes mPGES-1 and 15-PGDH, which could potentially be responsible for regulating PGE(2) production. Overall, our studies demonstrate that IL-4 has the capacity to inhibit COX-2 mRNA transcription in NSCLC cells and the inhibition of PGE(2) appears to be predominately COX-2 dependent.
Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center, and Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Xiaoyan
X
Cui
Seok-Chul
SC
Yang
Sherven
S
Sharma
Nathalie
N
Heuze-Vourc'h
Steven M
SM
Dubinett
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015847:Interleukin-4 / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis*; D010766:Phosphorylation; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
C508598:IL4 protein, human; D007375:Interleukin-1; D008565:Membrane Proteins; D012333:RNA, Messenger; D015847:Interleukin-4; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone