PECAM–1 (CD31)-gene expression is downregulated by TNF-α or Interferon (IFN-) but upregulated by TGF–1 in peripheral blood leukocytes

Introduction: Acute or chronic liver inflammations are characterized by a transmigration of inflammatory cells into the liver. CD–31 (PECAM–1) is an adhesion molecule considered as a marker of liver endothelial cells. It is expressed also on the surface of blood leukocytes and of tissue macrophages (e.g., Kupffer cells). Cells of the inflammatory infiltrate are PECAM–1-negative and loss of positivity is considered to be due to the interaction of the newly recruited cells with structures of the capillary wall within the “stressed” tissue. Methods and Materials: Changes of PECAM–1, ICAM–1 and VCAM–1 mRNA were studied in PHA or LPS treated human peripheral blood leukocytes (PBL), granulocytes and human monocytes. Experiments were performed in the presence or absence of anti-TNFα antibody. PBL were also treated with TNFα or with IFNγ and/or TGFβ. RNA was analysed by RT-PCR,protein by immunocytology and western blot. Results: Activation of PBL by PHA or LPS upregulated ICAM–1, VCAM–1 and downregulated PECAM–1-mRNA. The anti-TNFα antibody infliximab, by neutralizing TNFα and IFNγ production, suppressed PECAM–1 downregulation and ICAM–1, VCAM–1 upregulation. IFNγ or TNFα treatment reduced PECAM–1 in parallel with the induction of ICAM–1 and VCAM–1, whereas TGFβ upregulated PECAM–1 and reduced ICAM–1 and VCAM-mRNA counteracting the effect of TNFα or IFNγ. Similar results were obtained in human monocytes and in granulocyte by TNFα or IFNγ treatment. Conclusion: Activation of human leukocytes in vitro induces a PECAM–1 downregulation and a ICAM–1 and VCAM–1 upregulation through the action of TNFα and/or IFNγ. The changes can be reverted by adding an antibody against TNFα or TGF1 to the cell culture.This study highlights the importance of blocking TNFα in the therapy of acute rejection after liver transplantation or in patients suffering of chronic inflammatory liver diseases. TGF1 has an anti-inflammatory effect and is important for tissue repair and neoangiogenesis.