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. 1995 Sep;41(5):287–292. doi: 10.1007/BF01517216

Therapy with interleukin-2 induces the systemic release of phospholipase-A2

Gert Jan Wolbink 1,2,✉, Caspar Schalkwijk 3, Joke W Baars 4, John Wagstaff 4, Henk van den Bosch 3, C Erik Hack 1,2,5
PMCID: PMC11037621  PMID: 8536274

Abstract

Therapy with interleukin-2 (IL-2) induces remissions in some forms of cancer. This treatment however, is accompanied by side-effects which, in part, may be mediated by the formation of eicosanoids and plateletactivating factor. We investigated the systemic release of phospholipase A2 (PLA2), a rate-limiting enzyme in the formation of these lipid mediators, in patients receiving IL-2. In a pilot study of 4 patients we observed an increase in PLA2 activity in serial plasma samples obtained during the first day after a bolus infusion of IL-2, which increase closely correlated with that of antigen levels of secretory phospholipase A2 (sPLA2) as measured by enzyme-linked immunosorbent assay (r=0.92;P<0.001). In 20 patients, receiving 12×106−18×106 IU IL-2/m2, we then investigated the course of antigenic levels of sPLA2 in relation to those of the cytokines tumour necrosis factor α (TNF) and interleukin-6 (IL-6) (both cytokines may induce sPLA2 in vivo). From 4 h on, sPLA2 levels significantly increased, reaching a peak 24 h after the IL-2 infusion. Subsequent IL-2 infusions even induced a further increase of sPLA2. This increase of sPLA2 was presumably not due to a direct effect of IL-2 on, for example, hepatocytes, since this cytokine, in contrast to IL-1, IL-6, TNF and interferon γ, was not able to induce the synthesis of sPLA2 by Hep G2 cells in vitro. Consistent with this, plasma levels of TNF and IL-6 in the patients rose, reaching peak levels before a zenith of sPLA2 occurred, i.e at 2 h and 4 h after the start of the IL-2 infusion respectively. sPLA2 levels significantly correlated with the development of the side-effects increase in body weight (r=0.49;P<0.0001) and decrease in mean arterial blood pressure (r=0.40;P<0.0001). Moreover, maximum sPLA2 levels induced by IL-2 were higher in patients who had progressive disease after therapy than in patients who had stable disease or a partial response.

Key words: Interleukin-2 (IL-2), Interleukin-6 (IL-6), Tumour necrosis factor (TNF), Phospholipase A2 (PLA2), Cancer

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