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Migration of splenic lymphocytes promotes liver fibrosis through modification of T helper cytokine balance in mice

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Sustained liver injury causes liver fibrosis and eventually cirrhosis. Understanding the pathophysiological mechanisms of liver fibrosis and interventions in the fibrotic process is crucial for improving the prognosis of patients with chronic liver diseases. Although studies have shown that splenectomy suppresses liver fibrosis, the mechanism by which this occurs is poorly understood. The present study focuses on the immunological functions of the spleen to investigate its role in liver fibrosis.

Methods

BALB/c and severe combined immunodeficiency (SCID) mice underwent splenectomies or sham operations prior to induction of liver fibrosis with carbon tetrachloride or thioacetamide.

Results

Sirius red staining and hydroxyproline assays showed that splenectomy suppressed liver fibrogenesis in BALB/c mice. Reverse transcription PCR analysis of T helper type 1 (Th1) and T helper type 2 (Th2) cytokines demonstrated that splenectomy shifted the Th1/Th2 balance in the liver towards Th1 dominance. In SCID mice, the inhibitory effect on liver fibrosis was abrogated. The number of CD4+ T helper lymphocytes in the spleen decreased after liver injury. Green fluorescent protein positive (GFP+) splenocytes were transplanted into the spleens of syngeneic wild-type mice to trace their destination after fibrosis induction. GFP+CD4+ lymphocytes appeared in the liver after induction of fibrosis, and flow cytometry revealed the vast majority of them were Th2 lymphocytes. Transfer of splenocytes via the portal vein into syngeneic splenectomized mice cancelled the suppressive effect of splenectomy on liver fibrosis.

Conclusions

The present study demonstrated that Th2-dominant splenic lymphocytes migrate into the liver and promote liver fibrosis by shifting the cytokine balance towards Th2 dominance. Splenectomy suppresses the progression of fibrosis at least partly by restoring the Th1/Th2 balance.

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Abbreviations

BDL:

Bile duct ligation

GFP:

Green fluorescent protein

IL:

Interleukin

PBS:

Phosphate-buffered saline

qRT-PCR:

Quantitative reverse transcription PCR

SCID:

Severe combined immunodeficiency

α-SMA:

α-Smooth muscle actin

TAA:

Thioacetamide

Th1:

T helper type 1

Th2:

T helper type 2

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Acknowledgment

This work was supported by a grant from the Japan Society for the Promotion of Science: Grant-in-Aid for Scientific Research (B), no. 23390322.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan

    Kazutaka Tanabe, Kojiro Taura, Yukinori Koyama, Gen Yamamoto, Takahiro Nishio, Yukihiro Okuda, Kojiro Nakamura, Kan Toriguchi, Kenji Takemoto, Kenya Yamanaka, Satoru Seo, Etsuro Hatano & Shinji Uemoto

  2. Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Keiko Iwaisako

  3. Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto, 606-8501, Japan

    Masataka Asagiri

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  1. Kazutaka Tanabe
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  2. Kojiro Taura
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Correspondence to Kojiro Taura.

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Tanabe, K., Taura, K., Koyama, Y. et al. Migration of splenic lymphocytes promotes liver fibrosis through modification of T helper cytokine balance in mice. J Gastroenterol 50, 1054–1068 (2015). https://doi.org/10.1007/s00535-015-1054-3

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  • DOI: https://doi.org/10.1007/s00535-015-1054-3

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