title: Evidence of dual function of macrophage migration inhibitory factor relevant to tumor progression and regression.
abstract: Macrophage migration inhibitory factor (MIF) is known to play an important role in broad-spectrum inflammation and immune responses. To evaluate the role of MIF in tumor growth, we established transgenic (Tg) mice (ICR strain) driven by cytomegalovirus (CMV) enhancer and beta-actin promoter. We inoculated Tg mice in the back with murine sarcoma cell line S-180 cells. The tumor growth rate was more enhanced in Tg mice than in littermate non-Tg mice up to day 9 after tumor inoculation. Surprisingly, most tumors embedded on the back of Tg mice regressed at day 10 after inoculation and eventually disappeared. Tumor volumes of non-Tg mice incessantly increased until death. We reinoculated the Tg mice with S-180 cells, which had been recovered from the first challenge, and found that the tumor cells were completely rejected in all cases. To identify the effector cells that eradicated the tumor cells, we prepared spleen cells from tumor-bearing Tg mice and carried out cell lysis assay. The magnitude of cytolytic activity of spleen cells obtained from Tg mice was significantly higher against S-180 cells, as well as natural killer cell-sensitive YAC-1 cells, than was the activity of cells from non-Tg mice. Furthermore, we observed that CTL activity of Tg mice against S-180 cells was significantly decreased by the deletion of CD8+ T cells or NK cells. On the other hand, the deletion of CD4+ cells minimally affected the cytolytic activity. Taken together, these results suggest that MIF has the potential to promote tumor growth and angiogenesis in the early phase and, by contrast, this protein could activate CD8+ cytotoxic T cells and NK cells, leading to tumor regression.
authors.affiliation: Department of Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Jun
authors.initials: J
authors.lastname: Nishihira
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshiki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwabuchi
authors.forename: Chikako
authors.initials: C
authors.lastname: Iwabuchi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Masao
authors.initials: M
authors.lastname: Kondo
authors.forename: Bailong
authors.initials: B
authors.lastname: Sun
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sato
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000166:cytology; D018655:Lymphocyte Count; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger