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TLR5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β-Interleukin-1 Receptor Antagonist in Mice

43 Pages Posted: 23 Jan 2019

See all articles by Zixiong Zhou

Zixiong Zhou

Chonbuk National University - Biosafety Research Institute; Chonbuk National University - College of Veterinary Medicine

Jong-Won Kim

Chonbuk National University - Biosafety Research Institute; Chonbuk National University - College of Veterinary Medicine

Jing Qi

Chonbuk National University - Biosafety Research Institute; Chonbuk National University - College of Veterinary Medicine

Seong Kug Eo

Chonbuk National University - Biosafety Research Institute; Chonbuk National University - College of Veterinary Medicine

Chae Woong Lim

Chonbuk National University - Biosafety Research Institute; Chonbuk National University - College of Veterinary Medicine

Bumseok Kim

Chonbuk National University - Biosafety Research Institute; Chonbuk National University - College of Veterinary Medicine

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Abstract

Background: Bacterial flagellin, recognized by cell surface of toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in liver fibrosis is still unclear.  

Methods: Hepatotoxin- and cholestasis-induced liver fibrosis models were used in this study. Real-time PCR, Western blotting, and histopathologic analysis were performed to elucidate the underlying mechanism of TLR5 signaling in the pathogenesis of liver fibrosis.  

Findings: Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Notably, hepatic expression of interleukin-1 receptor antagonist (IL-1ra) and interferon (IFN) β was markedly increased in fibrotic livers upon flagellin treatment. Consistently, in vivo activation of TLR5 signaling significantly increased IFNβ and IL-1ra expression in the livers. Interestingly, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-α/β receptor-1 (IFNAR1)-deficient mice. Furthermore, hepatic expression of IL-1ra in the fibrotic livers of IFNAR1-deficient mice was significantly lower than those of WT mice. In support of these findings, flagellin-mediated IL-1ra production is not sufficient to alleviate the severity of hepatic fibro-inflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL-1ra showed significantly decreased cellular activation and its associated fibrogenic responses.

Interpretation: Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.  

Funding Statement: This research was supported by grant (NRF-2017R1D1A3B03030521, 2017R1A6A3A11032024) of the Basic Science Research Program through the National Research Foundation (NRF), funded by the Ministry of Education, Republic of Korea

Declaration of Interests: The authors declare that there are no conflicts of interests.

Ethics Approval Statement: Experimental procedures and animal management procedures were undertaken in accordance with the requirements of the Animal Care and Ethics Committees of Chonbuk National University. The animal facility of Chonbuk National University is fully accredited by the National Association of Laboratory Animal Care.

Keywords: Flagellin, TLR5, Liver fibrosis, Type I IFN, IL-1ra

Suggested Citation

Zhou, Zixiong and Kim, Jong-Won and Qi, Jing and Eo, Seong Kug and Lim, Chae Woong and Kim, Bumseok, TLR5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β-Interleukin-1 Receptor Antagonist in Mice (January 16, 2019). Available at SSRN: https://ssrn.com/abstract=3320129

Zixiong Zhou

Chonbuk National University - Biosafety Research Institute

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Chonbuk National University - College of Veterinary Medicine

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Jong-Won Kim

Chonbuk National University - Biosafety Research Institute

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Chonbuk National University - College of Veterinary Medicine

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Jing Qi

Chonbuk National University - Biosafety Research Institute

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Chonbuk National University - College of Veterinary Medicine

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Seong Kug Eo

Chonbuk National University - Biosafety Research Institute

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Chonbuk National University - College of Veterinary Medicine

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Chae Woong Lim

Chonbuk National University - Biosafety Research Institute

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Chonbuk National University - College of Veterinary Medicine

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Bumseok Kim (Contact Author)

Chonbuk National University - Biosafety Research Institute ( email )

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

Chonbuk National University - College of Veterinary Medicine ( email )

567, Baekje-daero
Jeonju-si, Jeollabuk-do
Korea, Republic of (South Korea)

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