title: Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells.
abstract: Programmed cell death protein 1 (PD-1) acts on PD-1 ligands (PD-L1 and PD-L2) to suppress activation of cytotoxic T lymphocytes. Interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) are co-expressed by T helper 17 (TH17) cells in many tumors. The purpose of this study was to test if IL-17 and TNF-α may synergistically induce PD-L1 expression in human prostate cancer LNCaP and human colon cancer HCT116 cell lines. We found that IL-17 did not induce PD-L1 mRNA expression, but up-regulated PD-L1 protein expression in HCT116 and LNCaP cells. TNF-α induced PD-L1 mRNA and protein expression in both cell lines. Neither IL-17 nor TNF-α induced PD-L2 mRNA or protein expression. IL-17 and TNF-α acted individually rather than cooperatively in induction of PD-L1 expression. IL-17 and/or TNF-α activated AKT, nuclear factor-κB (NF-κB), and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathways in HCT116 cells, whereas only NF-κB signaling was activated in LNCaP cells. NF-κB inhibitor could diminish PD-L1 protein expression induced by IL-17 and/or TNF-α in both HCT116 and LNCaP cell lines. ERK1/2 inhibitor could also reduce PD-L1 protein expression induced by IL-17 and/or TNF-α in HCT116 cells, while AKT inhibitor could abolish PD-L1 protein expression induced by IL-17 and/or TNF-α in LNCaP cells. These results suggest that IL-17 and TNF-α act individually rather than cooperatively through activation of NF-κB and ERK1/2 signaling to up-regulate PD-L1 expression in HCT116 cells, while the two inflammatory cytokines act through activation of NF-κB signaling, in the presence of AKT activity, to up-regulate PD-L1 expression in LNCaP cells.
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Gastroenterology, Wuchang Hospital, Wuhan 430063, China. Electronic address: wangxun0095@qq.com.
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China. Electronic address: ylyghost@gmail.com.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Clinical Medicine, The First Affiliated Hospital, Shanxi University of Chinese Medicine, Xianyang 712046, China. Electronic address: fhuang3@tulane.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: qzhang3@tulane.edu.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: sliu1@tulane.edu.
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: lma2@tulane.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Orthopaedic Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: zyou@tulane.edu.
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D060890:B7-H1 Antigen; D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Colon cancer; Interleukin-17; Programmed cell death protein 1 ligand 1; Prostate cancer; Tumor necrosis factor-α