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©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions
Abdel-Rahman N Zekri, Somaya El Deeb, Abeer A Bahnassy, Abeer M Badr, Mona S Abdellateif, Gamal Esmat, Hosny Salama, Marwa Mohanad, Ahmed Esam El-dien, Shimaa Rabah, Assmaa Abd Elkader
Abdel-Rahman N Zekri, Molecular Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
Somaya El Deeb, Abeer M Badr, Ahmed Esam El-dien, Shimaa Rabah, Assmaa Abd Elkader, Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
Abeer A Bahnassy, Department of Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
Mona S Abdellateif, Medical Biochemistry and Molecular Biology, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
Gamal Esmat, Hosny Salama, Department of Hepatology and Tropical Medicine, Faculty of Medicine, Cairo University, Cairo 11441, Egypt
Marwa Mohanad, Department of Biochemistry, Misr University for Science and Technology, 6th October 12945, Giza Governorate, Egypt
Author contributions: Zekri AN was the main supervisor, put forth the idea and planned of work, and performed data interpretation; El Deeb S supervised the biochemical work; Bahnassy AA supervised the flow cytometry work and revised the paper; Badr AM revised the paper; Abdellateif MS analyzed the data and wrote the paper; Esmat G and Salama H performed the medical care and the follow-up of patients; Mohanad M analyzed the data; El-dien AE performed the immunophenotyping; Rabah S and Abd Elkader A performed the ELISA work.
Institutional review board statement: The study was reviewed and approved for publication by our Institutional Reviewer.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.
Data sharing statement: The original anonymized dataset is available on request from the corresponding author at ncizekri@yahoo.com.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Abdel-Rahman N Zekri, MSc, PhD, Professor, Molecular Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Kasr Al-Aini Street, Fom El-Khaleeg, Cairo 11976, Egypt. ncizekri@yahoo.com
Telephone: +2-10-01413521 Fax: +2-202-23644720
Received: November 5, 2017
Peer-review started: November 6, 2017
First decision: November 27, 2017
Revised: December 24, 2017
Accepted: January 16, 2018
Article in press: January 16, 2018
Published online: March 21, 2018
AIM
To assess the levels of different immune modulators in patients with hepatocellular carcinoma (HCC), in relation to other hepatic diseases.
METHODS
Eighty-eight patients were included in the current study and represented patients with HCC (20), liver cirrhosis (28) and chronic hepatitis (CH; 25), and normal controls (NC; 15). Peripheral blood was isolated for immunophenotyping of active myeloid dendritic cells (mDCs; CD1c and CD40), mature inactive myeloid cells (CD1c and HLA), active plasmacytoid cells (pDCs; CD303 and CD40), mature inactive pDCs (CD30 and HLA), active natural killer (NK) cells (CD56 and CD161), active NK cells (CD56 and CD314) and inactive NK cells (CD56 and CD158) was done by flow cytometry. Serum levels of interleukin (IL)-2, IL-10, IL-12, IL-1β, interferon (IFN)-α, IFN-γ and tumor necrosis factor (TNF)-αR2 were assessed by ELISA.
RESULTS
Active mDCs (CD1C+/CD40+) and inactive mDCs (CD1c+/HLA+) were significantly decreased in HCC patients in relation to NC (P < 0.001). CD40+ expression on active pDCs was decreased in HCC patients (P < 0.001), and its level was not significantly changed among other groups. Inactive pDCs (CD303+/HLA+), inactive NKs (CD56+/CD158+) and active NKs (CD56+/CD161+) were not statistically changed among the four groups studied; however, the latter was increased in CH (P < 0.05). NKG2D was statistically decreased in HCC, CH and cirrhosis (P < 0.001), and it was not expressed in 63% (12/20) of HCC patients. There was significant decrease of IL-2, IFN-α and IFN-γ (P < 0.001), and a significant increase in IL-10, IL-1β, and TNF-αR2 (P <0.01, P < 0.001 and P < 0.001; respectively) in HCC patients. There was inverted correlation between IL-12 and IL-1β in HCC (r = -0.565, P < 0.01), with a strong correlation between pDCs (CD303+/CD40+) and NKs (CD56+/CD161+; r = 0.512, P < 0.05) as well as inactive mDCs (CD1c+/HLA+) and inactive NK cells (CD56+/CD158+; r = 0.945, P < 0.001).
CONCLUSION
NKG2D, CD40, IL-2 and IL-10 are important modulators in the development and progression of HCC.
Core tip: We assessed the levels of different immune modulatory cytokines and innate immune cells as natural killer (NK) cells and dendritic cells (DCs) in patients with disease progression of hepatocarcinogenesis. Our results showed significant down-regulation in active mDCs and pDCs expressing CD40 as well as NK cells expressing NKG2D. The expression of NKG2D on NKs was not expressed in 63% of hepatocellular carcinoma (HCC) patients. Also, there was significant decrease of interleukin (IL)-2, interferon-α and interferon-γ, and a significant increase in IL-10, IL-1β, and TNF-αR2 in HCC patients. These factors could be implicated in the pathogenesis of HCC, and represent attractive targets for therapy in chronic hepatitis C virus hepatitis and HCC.
