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

Int Immunopharmacol. 2007 Feb;7(2):140-51. doi: 10.1016/j.intimp.2006.09.021. Epub 2006 Oct 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dimethylhydrazine
  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Anticarcinogenic Agents / therapeutic use*
  • Arginase / genetics
  • Breast Neoplasms / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Carcinogens
  • Celecoxib
  • Cell Proliferation / drug effects
  • Concanavalin A / pharmacology
  • Cyclooxygenase 2 Inhibitors / therapeutic use*
  • Female
  • Intestinal Neoplasms / chemically induced
  • Intestinal Neoplasms / immunology*
  • Intestinal Neoplasms / pathology
  • Intestinal Neoplasms / prevention & control*
  • Membrane Proteins / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Nitric Oxide Synthase Type II / genetics
  • Pyrazoles / therapeutic use*
  • RNA, Messenger / metabolism
  • Spleen / cytology
  • Spleen / immunology
  • Sulfonamides / therapeutic use*


  • Adjuvants, Immunologic
  • Anticarcinogenic Agents
  • Carcinogens
  • Cyclooxygenase 2 Inhibitors
  • Membrane Proteins
  • Pyrazoles
  • RNA, Messenger
  • Sulfonamides
  • flt3 ligand protein
  • Concanavalin A
  • Nitric Oxide Synthase Type II
  • Arginase
  • 1,2-Dimethylhydrazine
  • Celecoxib