NONSMALL 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 E-2 (PGE(2)) modifies cytokine balance and inhibits host immunity, We hypothesized that a high level of PGE(2) p roduction by lung tumor cells is dependent on tumor cyclooxygenase (CO X)-2 expression, We found that PGE(2) production by A549 non-small cel l lung cancer (NSCLC) cells was elevated up to 50-fold in response to interleukin (IL)-1 beta, Reversal of IL-1 beta-induced PGE(2) producti on in A549 cells was achieved by specific pharmacological or antisense oligonucleotide inhibition of COX-2 activity or expression, In contra st, specific COX-1 inhibition was not effective, Consistent with these findings, IL-1 beta induced COX-2 mRNA expression and protein product ion in A549 cells, Specific inhibition of COX-2 abrogated the capacity of IL-1 beta-stimulated A549 cells to induce IL-10 in lymphocytes and macrophages, Furthermore, specific inhibition of A549 COX-2 reversed the tumor-derived PGE(2)-dependent inhibition of macrophage IL-12 prod uction when whole blood was cultured in tumor supernatants, Our result s indicate that lung tumor-derived PGE(2) plays a pivotal role in prom oting lymphocyte and macrophage IL-10 induction while simultaneously i nhibiting macrophage IL-12 production, Immunohistochemistry of human N SCLC tissues obtained from lung cancer resection specimens revealed cy toplasmic staining for COX-2 within tumor cells, This is the first des cription of functional COX-2 expression by NSCLC cells and the definit ion of a pathway whereby tumor COX-2 expression and a high level of PG E(2) production mediate profound alteration in cytokine balance in the lung cancer microenvironment.