title: Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion.
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.
authors.affiliation: Laboratory of Transplantation Immunology, Department of Pathology and Microbiology, 987660, University of Nebraska Medical Center, Omaha, NE 68198-7660, USA. jtalmadg@unmc.edu
authors.forename: James E
authors.initials: JE
authors.lastname: Talmadge
authors.forename: Keith C
authors.initials: KC
authors.lastname: Hood
authors.forename: Lori C
authors.initials: LC
authors.lastname: Zobel
authors.forename: Laura R
authors.initials: LR
authors.lastname: Shafer
authors.forename: Melissa
authors.initials: M
authors.lastname: Coles
authors.forename: Bela
authors.initials: B
authors.lastname: Toth
mesh_terms: D019813:1,2-Dimethylhydrazine; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001119:Arginase / Q000235:genetics; D001943:Breast Neoplasms / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002273:Carcinogens; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D005260:Female; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D011720:Pyrazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D000276:Adjuvants, Immunologic; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; C084881:flt3 ligand protein; D003208:Concanavalin A; D052247:Nitric Oxide Synthase Type II; D001119:Arginase; D019813:1,2-Dimethylhydrazine; D000068579:Celecoxib