title: Attenuation of IFN-γ-induced B7-H1 expression by 15-deoxy-delta(12,14)-prostaglandin J2 via downregulation of the Jak/STAT/IRF-1 signaling pathway.
abstract: OBJECTIVE
  B7-H1, which belongs to the B7 family of costimulatory molecules, is implicated in the ability of tumors to evade the host immune response. The development of evasion mechanisms within the tumor microenvironment may be responsible for poor therapeutic responses. In this manuscript, we report that the 15-deoxy-δ(12,14)-prostaglandin J2 (15d-PGJ2), peroxisome proliferator-activated receptor gamma (PPARγ) activator leads to the downregulation of the cancer-associated expression of B7-H1 in response to interferon-gamma (IFN-γ) and the associated signaling cascades.
  
  
  METHODS
  The expression of B7-H1 from IFN-γ-induced B16F10 melanoma cells was measured with flow cytometric analysis. The regulatory mechanisms of 15d-PGJ2 on cellular signaling pathways were examined using Western blot and electrophoretic mobility shift assays.
  
  
  RESULTS
  The flow cytometric analysis revealed that the B7-H1 costimulatory molecule is significantly upregulated in B16F10 melanoma cells by stimulation with IFN-γ. However, 15d-PGJ2 strongly downregulates B7-H1 expression in IFN-γ-stimulated B16F10 melanoma cells. Furthermore, the significant damping effect of 15d-PGJ2 on B7-H1 expression involves the inhibition of the tyrosine phosphorylation of Janus kinase (Jak) and signal transducer(s) and activator(s) of transcription (STAT) and, thereby, the interferon regulatory factor-1 (IRF-1) trans-activation of STAT. These effects of 15d-PGJ2 were not abrogated by the PPARγ antagonist GW9662, indicating that they occur through a PPARγ-independent mechanism.
  
  
  CONCLUSIONS
  In this study, we demonstrate that 15d-PGJ2 suppresses the IFN-γ-elicited expression of B7-H1 by the inhibition of IRF-1 transcription via the Jak/STAT signaling pathway through a PPARγ-independent mechanism in mouse melanoma cells.
authors: Department of Microbiology, College of Medicine, Inje University, Busan, Republic of Korea.
authors: Su-Kil
authors: SK
authors: Seo
authors: Department of Preventive Medicine, College of Medicine Kosin University, Busan, Republic of Korea.
authors: Dae-Il
authors: DI
authors: Seo
authors: Department of Physiology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea.
authors: Won Sun
authors: WS
authors: Park
authors: Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, Republic of Korea.
authors: Won-Kyo
authors: WK
authors: Jung
authors: Marine Biodiversity Institute of Korea, Sejong, Republic of Korea.
authors: Dae-Sung
authors: DS
authors: Lee
authors: Department of Microbiology, College of Medicine, Inje University, Busan, Republic of Korea.
authors: Sae-Gwang
authors: SG
authors: Park
authors: Department of Internal Medicine, Pusan Paik Hospital, College of Medicine Inje University, Busan, Republic of Korea.
authors: Jung Sik
authors: JS
authors: Choi
authors: Department of Pathology, Inje University College of Medicine, Busan, Republic of Korea.
authors: Mi-Seon
authors: MS
authors: Kang
authors: Department of Biochemistry, Dongeui University College of Korean Medicine, Busan, Republic of Korea.
authors: Young Hyun
authors: YH
authors: Choi
authors: Department of Microbiology, College of Medicine, Inje University, Busan, Republic of Korea.
authors: Inhak
authors: I
authors: Choi
authors: Department of Preventive Medicine, College of Medicine Kosin University, Busan, Republic of Korea. Electronic address: preventeer@hanmail.net.
authors: Byeng Chul
authors: BC
authors: Yu
authors: Department of Microbiology, College of Medicine, Inje University, Busan, Republic of Korea. Electronic address: cihima@inje.ac.kr.
authors: Il-Whan
authors: IW
authors: Choi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D050856:Interferon Regulatory Factor-1; D047495:PPAR gamma; D050791:STAT Transcription Factors; D007371:Interferon-gamma; D053612:Janus Kinases; D015230:Prostaglandin D2
keywords: 15-Deoxy-delta(12,14)-prostaglandin J(2) inhibits B7-H1 expression; B7-H1, 15-deoxy-δ(12,14)-prostaglandin J(2); Costimulatory molecules; Interferon regulatory factor-1; Peroxisome proliferator-activated receptor gamma; Signal transducer(s) and activator(s) of transcription