Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production.
Tumor-derived prostaglandin E2 (PGE2) modifies cytokine balance and inhibits host immunity. We hypothesized that a high level of PGE2 production by lung tumor cells is dependent on tumor cyclooxygenase (COX)-2 expression. We found that PGE2 production by A549 non-small cell lung cancer (NSCLC) cells was elevated up to 50-fold in response to interleukin (IL)-1beta. Reversal of IL-1beta-induced PGE2 production in A549 cells was achieved by specific pharmacological or antisense oligonucleotide inhibition of COX-2 activity or expression. In contrast, specific COX-1 inhibition was not effective. Consistent with these findings, IL-1beta induced COX-2 mRNA expression and protein production in A549 cells. Specific inhibition of COX-2 abrogated the capacity of IL-1beta-stimulated A549 cells to induce IL-10 in lymphocytes and macrophages. Furthermore, specific inhibition of A549 COX-2 reversed the tumor-derived PGE2-dependent inhibition of macrophage IL-12 production when whole blood was cultured in tumor supernatants. Our results indicate that lung tumor-derived PGE2 plays a pivotal role in promoting lymphocyte and macrophage IL-10 induction while simultaneously inhibiting macrophage IL-12 production. Immunohistochemistry of human NSCLC tissues obtained from lung cancer resection specimens revealed cytoplasmic staining for COX-2 within tumor cells. This is the first description of functional COX-2 expression by NSCLC cells and the definition of a pathway whereby tumor COX-2 expression and a high level of PGE2 production mediate profound alteration in cytokine balance in the lung cancer microenvironment.
Huang
M
M
Department of Medicine, UCLA School of Medicine and the West Los Angeles Veterans Affairs Medical Center, California 90073, USA.
Stolina
M
M
Sharma
S
S
Mao
J T
JT
Zhu
L
L
Miller
P W
PW
Wollman
J
J
Herschman
H
H
Dubinett
S M
SM
D000230:Adenocarcinoma / Q000201:enzymology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology; D051546:Cyclooxygenase 2; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007158:Immunologic Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology*; D008214:Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D016753:Interleukin-10; D018664:Interleukin-12; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases