Pentoxifylline inhibits granzyme B and perforin expression following T-lymphocyte activation by anti-CD3 antibody

• Published in: International journal of immunopharmacology 1996-11, Vol.18 (11), p.623-631
• Main Authors: Hoskin, David W., Phu, Tommy, Makrigiannis, Andrew P.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; CD3 Complex - physiology; Cell Division - drug effects; Cells, Cultured; Depression, Chemical; Fas ligand; granzyme B; Granzymes; Immunomodulators; In Vitro Techniques; Killer Cells, Lymphokine-Activated - drug effects; killer lymphocyte; Lymphocyte Activation - immunology; Male; Medical sciences; Membrane Glycoproteins - biosynthesis; Mice; Mice, Inbred C57BL; pentoxifylline; Pentoxifylline - pharmacology; Perforin; Pharmacology. Drug treatments; Polymerase Chain Reaction; Pore Forming Cytotoxic Proteins; Serine Endopeptidases - biosynthesis; Spleen; T-Lymphocytes - drug effects; Tumor Cells, Cultured
• ISSN: 0192-0561; 1879-3495
• DOI: 10.1016/S0192-0561(96)00069-0

Pentoxifylline (PTX), a methylxanthine derivative, is known to inhibit the production of the Th 1 cytokines interleukin-2, tumour necrosis factor-α and interferon-y. Because these cytokines play an important role in promoting the development of cell-mediated immunity, we hypothesized that PTX would also interfere with the generation of cytotoxic effector cells in response to an immunological stimulus. In this study we used a mouse model system to investigate the effect of PTX on the induction of non-specific killer lymphocytes by anti-CD3 monoclonal antibody. Anti-CD3-induced T-cell proliferation and the generation of anti-CD3-activated killer (AK) cells was inhibited in a dose-dependent fashion by PTX (25–100 gg/ml). The inhibitory effect of PTX could not be attributed to a defect in the recognition/adhesion phase of cytolysis because AK cells generated in the presence of PTX conjugated normally with P815 tumour target cells. However, AK cell expression of the cytoplasmic granule-associated cytolytic effector molecules granzyme B and perforin was markedly reduced when AK cells were induced in the presence of PTX. In contrast, PTX had no effect on AK cell expression of Fas ligand, a cell-surface cytolytic effector molecule which is involved in granule-independent cytotoxicity. PTX thus has a profound inhibitory effect in vitro on the induction of granule-dependent cytolytic effector mechanisms in a mouse model system.