Pentoxifylline inhibits integrin-mediated adherence of interleukin-2- activated human peripheral blood lymphocytes to human umbilical vein endothelial cells, matrix components, and cultured tumor cells.
Peripheral blood lymphocytes (PBLs) cultured in the presence of recombinant human interleukin-2 (rhIL-2) develop a natural killer (NK) cell phenotype (CD16+, CD56+, CD3-) and are referred to as lymphokine-activated killer cells (LAK). In developing the LAK phenotype, enhanced adherence to matrix components and endothelial cells have been described. In this report we investigated the functional behavior of adhesion receptors in rhIL-2-activated PBLs by in vitro adhesion assay and by flow cytometry. Compared to PBLs, IL-2-activated PBLs had increased integrin-mediated adherence to: (1) fibronectin (FN), (2) human umbilical vein endothelial (HUVE) cells, and (3) cultured melanoma and pancreatic tumor cell lines. This increase in adherence was mediated by increased surface expression of members of the beta 1 and beta 2 integrin subfamilies, as determined by flow cytometric analysis. No induction of an activation-dependent beta 1 (CD29) epitope was detected. We also investigated the effects of the methylxanthine derivative pentoxifylline (PTX) on PBLs and rhIL-2-activated PBL adhesion. PBLs co-cultivated in the presence of rhIL-2 (1,000 U/mL) and PTX exhibited reduced adherence to FN, HUVE and cultured tumor cell lines. This inhibition by PTX was concentration- and time-dependent. The increased expression of integrins induced by rhIL-2 was only in part inhibited by PTX, suggesting that PTX induced a subpopulation of integrins that are expressed but functionally inactive.
Kovach
N L
NL
Department of Medicine, University of Washington, Seattle 98195.
Lindgren
C G
CG
Fefer
A
A
Thompson
J A
JA
Yednock
T
T
Harlan
J M
JM
D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology*; D010431:Pentoxifylline / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D015815:Cell Adhesion Molecules; D005353:Fibronectins; D016023:Integrins; D007376:Interleukin-2; D010431:Pentoxifylline