RT Journal Article
SR Electronic
T1 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
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 1208
OP 1216
VO 58
IS 6
A1 Huang, Min
A1 Stolina, Marina
A1 Sharma, Sherven
A1 Mao, Jenny T.
A1 Zhu, Li
A1 Miller, Patrice W.
A1 Wollman, Jerome
A1 Herschman, Harvey
A1 Dubinett, Steven M.
YR 1998
UL http://cancerres.aacrjournals.org/content/58/6/1208.abstract
AB 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)-1β. Reversal of IL-1β-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-1β induced COX-2 mRNA expression and protein production in A549 cells. Specific inhibition of COX-2 abrogated the capacity of IL-1β-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. ©1998 American Association for Cancer Research.