Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion

James E. Talmadge, Keith C. Hood, Lori C. Zobel, Laura R. Shafer, Melissa Coles, Bela Toth

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme activity have shown chemopreventive activity in carcinogen-induced and transgenic rodent tumor models and clinically for colon cancer. However, the mechanism(s) by which COX-2 inhibitors reduce carcinogenesis remains controversial. We report herein that administration of the selective COX-2 inhibitor, celecoxib, significantly reduces the number of Gr1+CD11b+ immature myeloid suppressor cells (IMSCs) during chemoprevention of 1,2-dimethylhydrazine diHCl-(1,2-DMH-) induction of large intestinal tumors in Swiss mice. Celecoxib administration also increased splenic lymphatic number and tumor infiltration by lymphocytes. The 1,2-DMH induction of large intestinal tumors was associated with a four-fold increase in IMSCs, and a decrease in splenic T cell number and function. Concordant with the changes in the IMSC frequency, messenger ribonucleic acid (mRNA) levels of inducible nitric oxide synthase (NOS-2) and arginase (Arg) were increased in the spleen of the tumor-bearing mice and normalized by celecoxib administration. In addition to delaying tumor induction, reducing tumor number, and increasing lymphocyte infiltration of tumors, celecoxib therapy reversed CD4+ T cell loss, decreased IMSC numbers and increased mRNA levels of NOS-2 and Arg in the spleen. In summary, our results suggest that celecoxib chemoprevention of autochthonous intestinal tumors can regulate IMSCs and CD4+ T cell numbers.

Original languageEnglish (US)
Pages (from-to)140-151
Number of pages12
JournalInternational Immunopharmacology
Volume7
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • Carcinogenesis
  • Celecoxib
  • Chemoprevention
  • Dendritic cell
  • Immature myeloid suppressor cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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