title: A potential role for hydrocortisone in the positive regulation of IL-15-activated NK-cell proliferation and survival.
abstract: Although glucocorticoids (GCs) have been described as acting mainly as anti-inflammatory 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.
authors.affiliation: Cancer Immunology and Immunotherapy Center, Saint Savas Hospital, 171 Alexandras Ave, Athens 115 22, Greece. perez@ciic.gr
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Perez
authors.forename: Louisa G
authors.initials: LG
authors.lastname: Mahaira
authors.forename: Fillio J
authors.initials: FJ
authors.lastname: Demirtzoglou
authors.forename: Panagiota A
authors.initials: PA
authors.lastname: Sotiropoulou
authors.forename: Panayotis
authors.initials: P
authors.lastname: Ioannidis
authors.forename: Eleni G
authors.initials: EG
authors.lastname: Iliopoulou
authors.forename: Angelos D
authors.initials: AD
authors.lastname: Gritzapis
authors.forename: Nectaria N
authors.initials: NN
authors.lastname: Sotiriadou
authors.forename: Constantin N
authors.initials: CN
authors.lastname: Baxevanis
authors.forename: Michael
authors.initials: M
authors.lastname: Papamichail
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002051:Burkitt Lymphoma; D017252:CD3 Complex / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D019409:Interleukin-15 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D017252:CD3 Complex; D019002:CD56 Antigen; D004268:DNA-Binding Proteins; C508024:IL15RA protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D008894:Milk Proteins; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; C404226:TSC22D3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006854:Hydrocortisone