Differential effects of ether lipids on the activity and secretion of interleukin-1 and interleukin-2

Abstract

Alkyl lysophospholipids (ALP) are synthetic analogues of lysophosphatidylcholine and represent a new generation of antitumor drugs currently being tested in phase-I trials in patients with cancer. The present study reports the differential modulation of human immunocompetent cells in vitro by ALP. Serum-bound ALP effectively blocked the response of growth factor-dependent cells to interleukin-2 (IL-2), inhibited the cellular production and release of IL-2 and suppressed the comitogenic effect of interleukin-1 (IL-1) on mouse thymocytes. In contrast, ALP-primed, monocyte-derived macrophages (MO) lost their ability to release IL-1 in response to stimuli like lipopolysaccharides (LPS) during terminal maturation from monocytes. Supernatants from ALP-primed, LPS-induced MO possessed costimulatory as well as direct mitogenic activity. Neither ALP alone nor ALP-conditioned MO supernatants stimulated mouse thymocytes. Priming of MO by ET-18-OH, an ALP molecule not substituted in the sn-2 position, occurred at concentrations 4- to 16-fold higher than the most active compounds ET-18-OCH3 and the thioether analogue BM 41.440. ALP also primed MO for subsequent activation of tumor cytotoxicity by LPS and interferon-gamma. IL-1 has multiple biological activities in common with ALP, and it may mediate antitumor activity and other ALP effects in vivo. The ability of ALP to induce differential immunomodulation, as demonstrated in this study, may make ALP worthy of study for the therapy of both autoimmune and neoplastic disease.