A potential role for hydrocortisone in the positive regulation of IL-15-activated NK-cell proliferation and survival

Although glucocorticoids (GCs) have been described as acting mainly as antiinflammatory and immunosuppressive drugs, they may also positively influence the immune system. In the present study, we demonstrate for the first time that hydrocortisone (HC), in synergy with interleukin-15 (IL-15), induces a dramatic increase in the expansion of peripheral blood-derived CD56(+) cells, favoring the preferential outgrowth of classical natural killer (CD56(+)CD3(-) NK) over CD56(+)CD3(+) natural killer T (NKT) cells. HC plus IL-15-driven CD56(+) cells exhibited an increased potential for cytokine production with no impairment in their NK- and lymphokine-activated killer (LAK) activities. Elevated levels of GC-induced leucine zipper protein (GILZ) messenger RNA (mRNA) were detected in both NK and NKT cells cultured with HC and IL-15, in comparison to IL-15 alone. Phosphorylation status of signal transducer and activator of transcription 5 (STAT5) was not affected by the presence of HC in either of the populations. On the contrary, HC differentially affected the IL-2/IL-15R beta- and gamma-chain surface expression and the phosphorylation levels of extracellular signal-regulated kinases 1/2 (ERK1/2) in IL-15-activated NK and NKT cells. Our data ascribe a novel role to GCs on mature NK-cell expansion and function and open new perspectives for their use in cellular adoptive cancer immunotherapy. (c) 2005 by The American Society of Hematology.