title: Interleukin-17 and prostaglandin E2 are involved in formation of an M2 macrophage-dominant microenvironment in lung cancer.
abstract: BACKGROUND
  Tumor-associated macrophages (TAMs) are divided into M1 and M2 macrophages. M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth and metastasis. The aim of this study was to examine the possible causes leading to the formation of an M2-macrophage-dominant tumor microenvironment in non-small-cell lung cancer.
  
  
  METHODS
  Forty-eight archived lung tumor samples were examined for the expression of interleukin-17 (IL-17) receptors, IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC), and the number of TAMs using immunohistochemical staining. Twenty fresh lung tumors and matched normal lung tissues were examined for expression of IL-17, cyclooxygenase-2, and prostaglandin E2 (PGE2), using enzyme-linked immunosorbent assay and Western blot analysis. Macrophage-migration assays were performed using fresh lung tumor tissues and IL-17 as chemoattractants. Induction of M2-macrophage differentiation was analyzed using real-time quantitative polymerase chain reaction.
  
  
  RESULTS
  TAMs expressed IL-17RA and IL-17RC. Lung tumors expressed higher levels of IL-17, cyclooxygenase-2, and PGE2, compared with normal lung tissues. Lung tumor tissues attracted migration of mouse RAW264.7 macrophages and primary peritoneal macrophages through IL-17, which was mediated by IL-17RA and IL-17RC. IL-17 did not induce either M1- or M2-macrophage differentiation. However, human lung cancer A549 cells strongly induced M2-macrophage differentiation of RAW264.7 macrophages when the two cell lines were cocultured. The inductive factor secreted by A549 cells was identified to be PGE2.
  
  
  CONCLUSIONS
  IL-17 recruits macrophages, and PGE2 induces M2-macrophage differentiation, hence the increased levels of IL-17 and PGE2 in lung cancer contribute to the formation of an M2-macrophage-dominant tumor microenvironment.
authors.affiliation: Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Lunxu
authors.initials: L
authors.lastname: Liu
authors.forename: Dongxia
authors.initials: D
authors.lastname: Ge
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.forename: Jiandong
authors.initials: J
authors.lastname: Mei
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Ren
authors.forename: Hu
authors.initials: H
authors.lastname: Liao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D020381:Interleukin-17 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011379:Prognosis; D018123:Receptors, Interleukin / Q000502:physiology; D053722:Receptors, Interleukin-17 / Q000502:physiology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; C491673:Il17ra protein, mouse; C508527:Il17rc protein, mouse; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D051546:Cyclooxygenase 2; D015232:Dinoprostone