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Specific Inhibition of Cyclooxygenase 2 Restores Antitumor Reactivity by Altering the Balance of IL-10 and IL-12 Synthesis

Marina Stolina, Sherven Sharma, Ying Lin, Mariam Dohadwala, Brian Gardner, Jie Luo, Li Zhu, Mitchell Kronenberg, Patrice W. Miller, Joseph Portanova, Jason C. Lee and Steven M. Dubinett
J Immunol January 1, 2000, 164 (1) 361-370; DOI: https://doi.org/10.4049/jimmunol.164.1.361
Marina Stolina
*UCLA-Wadsworth Pulmonary Laboratory and
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Sherven Sharma
*UCLA-Wadsworth Pulmonary Laboratory and
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Ying Lin
*UCLA-Wadsworth Pulmonary Laboratory and
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Mariam Dohadwala
*UCLA-Wadsworth Pulmonary Laboratory and
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Brian Gardner
*UCLA-Wadsworth Pulmonary Laboratory and
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Jie Luo
*UCLA-Wadsworth Pulmonary Laboratory and
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Li Zhu
*UCLA-Wadsworth Pulmonary Laboratory and
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Mitchell Kronenberg
§La Jolla Institute of Allergy and Immunology, San Diego, CA 92121
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Patrice W. Miller
*UCLA-Wadsworth Pulmonary Laboratory and
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Joseph Portanova
‡G. D. Searle, St. Louis, MO 63167; and
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Jason C. Lee
*UCLA-Wadsworth Pulmonary Laboratory and
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Steven M. Dubinett
*UCLA-Wadsworth Pulmonary Laboratory and
†Jonsson Comprehensive Cancer Center, University of California, Los Angeles, School of Medicine and West Los Angeles Veterans Affairs Medical Center, Los Angeles, CA 90073;
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Abstract

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.

  • Received July 6, 1999.
  • Accepted October 8, 1999.
  • Copyright © 2000 by The American Association of Immunologists
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The Journal of Immunology: 164 (1)
The Journal of Immunology
Vol. 164, Issue 1
1 Jan 2000
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Specific Inhibition of Cyclooxygenase 2 Restores Antitumor Reactivity by Altering the Balance of IL-10 and IL-12 Synthesis
Marina Stolina, Sherven Sharma, Ying Lin, Mariam Dohadwala, Brian Gardner, Jie Luo, Li Zhu, Mitchell Kronenberg, Patrice W. Miller, Joseph Portanova, Jason C. Lee, Steven M. Dubinett
The Journal of Immunology January 1, 2000, 164 (1) 361-370; DOI: 10.4049/jimmunol.164.1.361

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Specific Inhibition of Cyclooxygenase 2 Restores Antitumor Reactivity by Altering the Balance of IL-10 and IL-12 Synthesis
Marina Stolina, Sherven Sharma, Ying Lin, Mariam Dohadwala, Brian Gardner, Jie Luo, Li Zhu, Mitchell Kronenberg, Patrice W. Miller, Joseph Portanova, Jason C. Lee, Steven M. Dubinett
The Journal of Immunology January 1, 2000, 164 (1) 361-370; DOI: 10.4049/jimmunol.164.1.361
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