Pentoxifylline suppresses interleukin-2-mediated activation of immature human natural killer cells by inhibiting endogenous tumor necrosis factor-alpha secretion.
We recently reported that immature human peripheral blood-derived natural killer (NK) cells, the free NK subset, can be activated by interleukin-2 (IL-2) to become killer cells and to undergo proliferation. Activation by IL-2 is dependent on endogenous secretion of tumor necrosis factor-alpha (TNF-alpha) by the free cells. Because pentoxifylline (PTX) inhibits TNF-alpha synthesis and secretion in monocytes, we hypothesized that PTX may also inhibit TNF-alpha secretion by NK cells and thus would inhibit IL-2-mediated activation of free cells. The free NK cells were separated from purified NK cells by flow cytometry and cell sorting of non-target binding cells. IL-2-mediated secretion of TNF-alpha by the free cells was inhibited by PTX. In the presence of PTX, IL-2-mediated activation of free cells into cytotoxic function, proliferation, and recruitment of binder and killer cells was markedly inhibited. Also, PTX inhibited IL-2-triggered upregulation of the expression of CD69, CD25, ICAM-1, and p75TNF-R on the cell surface. These findings demonstrate that PTX has a marked suppression on IL-2-mediated activation of immature free NK cells and that the suppression is due, in large part, to PTX-mediated inhibition of endogenous TNF-alpha secretion. The implication of these findings in the clinical use of PTX for therapy is discussed.
Jewett
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A
Department of Microbiology and Immunology, UCLA School of Medicine 90024.
Bonavida
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B
D000954:Antigens, Surface / Q000276:immunology; D002455:Cell Division; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010431:Pentoxifylline / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D015854:Up-Regulation
D000954:Antigens, Surface; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline