Migration of splenic lymphocytes promotes liver fibrosis through modification of T helper cytokine balance in mice.
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.
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan. tanabe75@kuhp.kyoto-u.ac.jp.
Kazutaka
K
Tanabe
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan. ktaura@kuhp.kyoto-u.ac.jp.
Kojiro
K
Taura
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Yukinori
Y
Koyama
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Gen
G
Yamamoto
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Takahiro
T
Nishio
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Yukihiro
Y
Okuda
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Kojiro
K
Nakamura
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Kan
K
Toriguchi
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Kenji
K
Takemoto
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Kenya
K
Yamanaka
Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Keiko
K
Iwaisako
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Satoru
S
Seo
Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.
Masataka
M
Asagiri
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Etsuro
E
Hatano
Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan.
Shinji
S
Uemoto
D000818:Animals; D002465:Cell Movement; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology*
D016207:Cytokines
Liver fibrosis; Splenectomy; T helper lymphocyte