Pentoxifylline inhibits granzyme B and perforin expression following T-lymphocyte activation by anti-CD3 antibody.
Pentoxifylline (PTX), a methylxanthine derivative, is known to inhibit the production of the TH1 cytokines interleukin-2, tumour necrosis factor-alpha and interferon-gamma. 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 micrograms/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 eontrast, 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.
Hoskin
D W
DW
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. dwhoskin@is.dal.ca
Phu
T
T
Makrigiannis
A P
AP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D053804:Granzymes; D066298:In Vitro Techniques; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000494:pharmacology*; D054353:Perforin; D016133:Polymerase Chain Reaction; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000096:biosynthesis*; D013154:Spleen; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; D010431:Pentoxifylline