title: COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in ApcMin/+ mouse polyps.
abstract: Macrophages are a major component of tumor stroma. Tumor-associated macrophages (TAMs) show anti- (M1) or protumor (M2) functions depending on the cytokine milieu of the tumor microenvironment. Cyclooxygenase-2 (COX-2) is constitutively expressed in a variety of tumors including colorectal cancer. TAMs are known to be a major source of COX-2 in human and mice intestinal tumors. COX-2 inhibitor reduces the number and size of intestinal adenomas in familial adenomatous polyposis patients and Apc(Min/+) mice. Although COX-2 inhibitor is thought to regulate cancer-related inflammation, its effect on TAM phenotype remains unknown. Here, we examined the effects of COX-2 inhibition on TAM phenotype and cytokine expression both in vivo and in vitro. Firstly, the selective COX-2 inhibitor celecoxib changed the TAM phenotype from M2 to M1, in proportion to the reduction in number of Apc(Min/+) mouse polyps. Concomitantly, the expression of M1-related cytokine interfron (IFN)-γ was significantly upregulated by celecoxib, although the M2-related cytokines interleukin (IL)-4, IL-13 and IL-10 were not significantly altered. Secondly, IFN-γ treatment attenuated M2 phenotype of mouse peritoneal macrophages and oriented them to M1 even in the presence of M2-polarizing cytokines such as IL-4, IL-13 and IL-10. Thus, our results suggest that COX-2 inhibition alters TAM phenotype in an IFN-γ-dependent manner and subsequently may reduce intestinal tumor progression.
authors: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto606-8507, Japan.
authors: Yuki
authors: Y
authors: Nakanishi
authors: Masato
authors: M
authors: Nakatsuji
authors: Hiroshi
authors: H
authors: Seno
authors: Shoko
authors: S
authors: Ishizu
authors: Reiko
authors: R
authors: Akitake-Kawano
authors: Keitaro
authors: K
authors: Kanda
authors: Taro
authors: T
authors: Ueo
authors: Hideyuki
authors: H
authors: Komekado
authors: Mayumi
authors: M
authors: Kawada
authors: Manabu
authors: M
authors: Minami
authors: Tsutomu
authors: T
authors: Chiba
mesh_terms: D000818:Animals; D016764:Cell Polarity; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics; D005260:Female; D017491:Genes, APC; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D010641:Phenotype; D018418:Th2 Cells / Q000276:immunology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D007371:Interferon-gamma