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CD56⁺ Cells Induce Steroid Resistance in B Cells Exposed to IL-15¹

Qing Xu^*, Elena Goleva^*, Liang-Shiou Ou^*,, Ling-Bo Li^* and Donald Y. M. Leung^2,*,

^* Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80262; and Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Children’s Hospital, Taoyuan, Taiwan

Interleukin-2 can induce steroid resistance in T cells. IL-15 shares biological activities with IL-2, as both cytokines use IL-2R 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.