Z Gastroenterol 2009; 47 - P1_36
DOI: 10.1055/s-0029-1191790

Deletion of the platelet derived chemokine PF4 (CXCL4) limits liver fibrosis in vivo

M Moreno Zaldivar 1, K Pauels 1, M Berres 1, P Schmitz 1, N Gassler 2, C Weber 3, R Weiskirchen 4, C Trautwein 1, HE Wasmuth 1
  • 1Medizinische Klinik III, Universitätsklinikum der RWTH Aachen
  • 2Institut für Pathologie, Universitätsklinikum der RWTH Aachen
  • 3Institut für Molekulare Herzkreislaufforschung, Universitätsklinikum der RWTH Aachen
  • 4Institut für Klinische Chemie und Pathobiochemie, Universitätsklinikum der RWTH Aachen

Aims: Chemokines are inflammatory mediators during acute and chronic liver injury. The chemokine PF4 (CXCL4) is the only chemokine which is mainly secreted by platelets. PF4 has been shown to interact with RANTES (CCL5), thereby increasing monocyte arrest to endothelium. As RANTES has been shown to stimulate hepatic stellate cells and platelets are thought to contribute to liver fibrosis, PF4 might be an interesting novel mediator of liver injury.

Methods: We induced liver fibrosis by CCl4 (6 weeks) and TAA (6 weeks) in PF4-/- mice and wild-type littermates. Fibrosis was analyzed by morphological staging of histology (sirius red staining) and hydroxyproline measurement in liver samples. Recruitment of immune cells (T cells, NK cells, NKT cells) to the liver was assessed by FACS. Additionally, the intrahepatic mRNA expression of fibrosis related genes (Collagen Ia1, TIMP-1, TGF-b, MMP-9) was determined by quantitative RT-PCR. In vitro, the stellate cell line LX-2 was stimulated with PF4 alone or in combination with RANTES and proliferation was determined by BrdU incorporation.

Results: Genetic deletion of PF4 resulted in a significantly reduced degree of fibrosis as assessed by liver histology and hydroxyproline content in both injury models (all P <0.01). FACS analysis revealed significantly reduced numbers of T cells in both models in PF4-/- mice compared to wild-type mice (all P <0.03). Treated PF4-/- mice had significantly reduced mRNA expression of fibrosis related genes (Collagen Ia1, TIMP-1, TGF-b; all P <0.05), while MMP-9 mRNA expression was not different. In vitro, PF4 alone did not induce proliferation of LX2-cells but significantly enhanced RANTES induced proliferation of stellate cells.

Conclusions: These results identify the platelet derived chemokine PF4 as a novel mediator of liver fibrogenesis in mice. The antifibrotic effects in PF4-/- mice may be caused by lack of interaction with RANTES and reduced stellate cell activation.

PF4 - chemokines - liver fibrosis - platelets