Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis.
Cyclooxygenase-2 (COX-2), the enzyme at the rate-limiting step of prostanoid production, has been found to be overexpressed in human lung cancer. To evaluate lung tumor COX-2 modulation of antitumor immunity, we studied the antitumor effect of specific genetic or pharmacological inhibition of COX-2 in a murine Lewis lung carcinoma (3LL) model. Inhibition of COX-2 led to marked lymphocytic infiltration of the tumor and reduced tumor growth. Treatment of mice with anti-PGE2 mAb replicated the growth reduction seen in tumor-bearing mice treated with COX-2 inhibitors. COX-2 inhibition was accompanied by a significant decrement in IL-10 and a concomitant restoration of IL-12 production by APCs. Because the COX-2 metabolite PGE2 is a potent inducer of IL-10, it was hypothesized that COX-2 inhibition led to antitumor responses by down-regulating production of this potent immunosuppressive cytokine. In support of this concept, transfer of IL-10 transgenic T lymphocytes that overexpress IL-10 under control of the IL-2 promoter reversed the COX-2 inhibitor-induced antitumor response. We conclude that abrogation of COX-2 expression promotes antitumor reactivity by restoring the balance of IL-10 and IL-12 in vivo.
Stolina
M
M
UCLA-Wadsworth Pulmonary Laboratory, University of California, Los Angeles, School of Medicine, West Los Angeles Veterans Affairs Medical Center 90073, USA.
Sharma
S
S
Lin
Y
Y
Dohadwala
M
M
Gardner
B
B
Luo
J
J
Zhu
L
L
Kronenberg
M
M
Miller
P W
PW
Portanova
J
J
Lee
J C
JC
Dubinett
S M
SM
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D007527:Isoenzymes; D016753:Interleukin-10; D018664:Interleukin-12; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone