Kazutaka Tanabe1, Kojiro Taura2, Yukinori Koyama3, Gen Yamamoto3, Takahiro Nishio3, Yukihiro Okuda3, Kojiro Nakamura3, Kan Toriguchi3, Kenji Takemoto3, Kenya Yamanaka3, Keiko Iwaisako4, Satoru Seo3, Masataka Asagiri5, Etsuro Hatano3, Shinji Uemoto3. 1. Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan. tanabe75@kuhp.kyoto-u.ac.jp. 2. Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan. ktaura@kuhp.kyoto-u.ac.jp. 3. Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan. 4. Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. 5. Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto, 606-8501, Japan.
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.
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 SCIDmice, 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.
Entities:
Keywords:
Liver fibrosis; Splenectomy; T helper lymphocyte
Authors: M J Czaja; F R Weiner; S Takahashi; M A Giambrone; P H van der Meide; H Schellekens; L Biempica; M A Zern Journal: Hepatology Date: 1989-11 Impact factor: 17.425
Authors: Steven C Katz; Kristin Ryan; Naseem Ahmed; George Plitas; Umer I Chaudhry; T Peter Kingham; Seema Naheed; Cang Nguyen; Ponnandai Somasundar; N Joseph Espat; Richard P Junghans; Ronald P Dematteo Journal: J Immunol Date: 2011-06-22 Impact factor: 5.422
Authors: A W Cheever; M E Williams; T A Wynn; F D Finkelman; R A Seder; T M Cox; S Hieny; P Caspar; A Sher Journal: J Immunol Date: 1994-07-15 Impact factor: 5.422
Authors: Filip K Swirski; Matthias Nahrendorf; Martin Etzrodt; Moritz Wildgruber; Virna Cortez-Retamozo; Peter Panizzi; Jose-Luiz Figueiredo; Rainer H Kohler; Aleksey Chudnovskiy; Peter Waterman; Elena Aikawa; Thorsten R Mempel; Peter Libby; Ralph Weissleder; Mikael J Pittet Journal: Science Date: 2009-07-31 Impact factor: 47.728