Short‐term exposure to oleandrin enhances responses to IL ‐8 by increasing cell surface IL ‐8 receptors

Background and Purpose One of the first steps in host defence is the migration of leukocytes. IL ‐8 and its receptors are a chemokine system essential to such migration. Up‐regulation of these receptors would be a viable strategy to treat dysfunctional host defence. Here, we studied the effects of the plant glycoside oleandrin on responses to IL‐8 in a human monocytic cell line. Experimental Approach U937 cells were incubated with oleandrin (1‐200 ng mL −1 ) for either 1 h (pulse) or for 24 h (non‐pulse). Apoptosis; activation of NF‐κB, AP‐1 and NFAT; calcineurin activity and IL‐8 receptors (CXCR1 and CXCR2) were measured using Western blotting, RT‐PCR and reporter gene assays. Key Results Pulse exposure to oleandrin did not induce apoptosis or cytoxicity as observed after non‐pulse exposure. Pulse exposure enhanced activation of NF‐κB induced by IL‐8 but not that induced by TNF‐α , IL ‐1, EGF or LPS . Exposure to other apoptosis‐inducing compounds (azadirachtin, resveratrol, thiadiazolidine, or benzofuran) did not enhance activation of NF ‐κB. Pulse exposure to oleandrin increased expression of IL‐8 receptors and chemotaxis, release of enzymes and activation of NF ‐κB, NFAT and AP‐1 along with increased IL ‐8‐mediated calcineurin activation, and wound healing. Pulse exposure increased numbers of cell surface IL‐8 receptors. Conclusions and Implications Short‐term (1 h; pulse) exposure to a toxic glycoside oleandrin, enhanced biological responses to IL‐8 in monocytic cells, without cytoxicity. Pulse exposure to oleandrin could provide a viable therapy for those conditions where leukocyte migration is defective.