CD56+ cells induce steroid resistance in B cells exposed to IL-15.
Interleukin-2 can induce steroid resistance in T cells. IL-15 shares biological activities with IL-2, as both cytokines use IL-2Rgamma for signal transduction. We therefore sought to determine whether IL-15 contributes to induction of PBMC corticosteroid resistance. Surprisingly, we found that incubation of unfractionated PBMC with IL-15 for 48 h resulted in the inhibition of glucocorticoid receptor (GCR) nuclear translocation in response to dexamethasone (DEX) treatment in CD19-positive B cells significantly greater than CD19-negative non-B cells (p < 0.01). However, pure B cells incubated with IL-15 responded normally with nuclear translocation of GCR in response to steroids, but failed to translocate GCR when they were grown in the presence of CD19(-) cells. Coculture of B cells with CD3(+) (T cells), CD14(+) (monocytes), or CD56(+) (NK and NKT cells) in the presence of IL-15 revealed that only CD56(+) cells contributed to the steroid insensitivity of B cells. IL-15 stimulation significantly increased production of IL-4 by CD56(+) cells (p < 0.02). Treatment of purified B cells with combination IL-15/IL-4 resulted in abrogation of glucocorticoid receptor nuclear translocation and the inability of DEX to suppress cytokine production by B cells. In the presence of IL-4-neutralizing Ab, when B cells were cocultured with CD56(+) cells and IL-15, the B cells were found to be steroid sensitive, i.e., DEX induced GCR nuclear translocation. This study demonstrates that B cells develop steroid resistance in the presence of CD56(+) cells after IL-15 stimulation. Furthermore, IL-15 and IL-4 have the capacity to induce B cell insensitivity to steroids.
Xu
Qing
Q
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Goleva
Elena
E
Ou
Liang-Shiou
LS
Li
Ling-Bo
LB
Leung
Donald Y M
DY
D001402:B-Lymphocytes / Q000187:drug effects*; D019002:CD56 Antigen / Q000032:analysis*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000502:physiology*
D019002:CD56 Antigen; D019409:Interleukin-15; D015850:Interleukin-6; D015847:Interleukin-4; D003907:Dexamethasone