title: Interferon gamma induced by resveratrol analog, HS-1793, reverses the properties of tumor associated macrophages.
abstract: Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on their activation state. Tumor-associated macrophages (TAM) are a kind of alternatively activated M2 macrophage, which may contribute to tumor progression. Following our previous study to evaluate the anti-tumor effect of a synthetic resveratrol analog HS-1793, the current study demonstrated that HS-1793 treatment significantly increased IFN-γ secreting cells in splenocytes and decreased CD206+ macrophage infiltration compared to CD68+ cells in the tumor site with a higher expression of IFN-γ. As these results suggested that IFN-γ increased locally at the tumor sites could modulate the status of TAM, we designed an in vitro model to study macrophage morphology and functions in relation to the tumor microenvironment. Human monocytic cell line THP-1 cells stimulated with phorbol-12-myristate-13-acetate (PMA) differentiated to macrophages with M2-like phenotypes. TAM-like properties of CD206(high), CD204(high), IL-10(high), TGF-β(high), IL-6(low), IL-12(low), VEGF(high), and MMP-9(high) and promotion of tumor cell invasion were more pronounced in M-2-polarized THP-1 macrophages generated by differentiating THP-1 cells with PMA and subsequently polarizing them with Th2 cytokines (IL-4/IL-13). Upon IFN-γ exposure, THP-1-derived TAM changed their phenotypes to the M-1-like morphology and intracellular granular pattern with an expression of an increased level of proinflammatory and immunostimulatory cytokines and a reduced level of immunosuppressive and tumor progressive mediators. These results explain the underlying mechanism of the anti-tumor activity of HS-1793. The elevated level of IFN-γ production after HS-1793 treatment evoked reprogramming of M-2 phenotype TAM, which efficiently countered the immunosuppressive and tumor progressive influences of TAM.
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Jeong
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: Kwangmo
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: You Soo
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: You Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Department of Orthopedic Surgery, Dong-A University College of Medicine, Daeshingongwon-gil 32, Seo-gu, Busan 602-714, Republic of Korea.
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Orthopedic Surgery, Dong-A University College of Medicine, Daeshingongwon-gil 32, Seo-gu, Busan 602-714, Republic of Korea.
authors.forename: Kyu Yeol
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Dong-A University College of Medicine, Daeshingongwon-gil 32, Seo-gu, Busan 602-714, Republic of Korea. Electronic address: mhjeong@dau.ac.kr.
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea. Electronic address: sailorjo@dirams.re.kr.
authors.forename: Wol Soon
authors.initials: WS
authors.lastname: Jo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D007371:Interferon-gamma / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D009284:Naphthols / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D012118:Resorcinols / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes
chemical_list: C523393:4-(6-hydroxy-2-naphthyl)-1,3-benzenediol; D009284:Naphthols; D012118:Resorcinols; D013267:Stilbenes; D007371:Interferon-gamma; D000077185:Resveratrol
keywords: HS-1793; IFN-γ; M-2 polarized macrophages; THP-1-derived macrophages; Tumor progression; Tumor-associated macrophages