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Immunology

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

Min Huang, Marina Stolina, Sherven Sharma, Jenny T. Mao, Li Zhu, Patrice W. Miller, Jerome Wollman, Harvey Herschman and Steven M. Dubinett
Min Huang
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Marina Stolina
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Sherven Sharma
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Jenny T. Mao
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Li Zhu
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Patrice W. Miller
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Jerome Wollman
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Harvey Herschman
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Steven M. Dubinett
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DOI:  Published March 1998
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Abstract

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.

Footnotes

  • ↵1 This work is supported by NIH Grants CA71818 and GM24797, the American Lung Association, Merit Review Research Funds from the Department of Veterans Affairs, and the Helen Neufeld Research Career Development Award (Stop Cancer Award). M. H. was supported by the American Lung Association of California Young Investigator Award and NIH Institutional Training Grant in Tumor Immunology CA09120. S. S. was supported by a Parker B. Francis Fellowship from the Francis Families Foundation. M. S. and J. T. M. were supported by NIH Institutional Training Grant in Pulmonary Medicine HL07104. S. M. D. is a Career Investigator of the American Lung Association.

  • ↵2 To whom requests for reprints should be addressed, at Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCLA School of Medicine, West Los Angeles Veterans Affairs Medical Center, 111Q, 11301 Wilshire Boulevard, Los Angeles, CA 90073, Phone: (310) 794-6566; Fax: (310) 268-4712; E-mail: sdubinet@ucla.edu.

  • Received November 6, 1997.
  • Accepted January 29, 1998.
  • ©1998 American Association for Cancer Research.
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March 1998
Volume 58, Issue 6
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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
Min Huang, Marina Stolina, Sherven Sharma, Jenny T. Mao, Li Zhu, Patrice W. Miller, Jerome Wollman, Harvey Herschman and Steven M. Dubinett
Cancer Res March 15 1998 (58) (6) 1208-1216;

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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
Min Huang, Marina Stolina, Sherven Sharma, Jenny T. Mao, Li Zhu, Patrice W. Miller, Jerome Wollman, Harvey Herschman and Steven M. Dubinett
Cancer Res March 15 1998 (58) (6) 1208-1216;
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