Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2– versus IL-15–activated NK cells

Abstract

Upon specific recognition of HLA class I molecules, the HLA class I-specific inhibitory receptors suppress NK-cell cytolytic activity, whereas target-cell lysis will require a partial or complete downregulation of HLA class I molecules. [3][4][5][6][7] Several structurally different activating receptors are involved in NK cell-mediated cytotoxicity. The CD16 receptor, expressed on the majority of peripheral-blood NK cells, mediates antibodydependent cytotoxicity (ADCC) against IgG-coated target cells. CD16 associates with CD3 and Fc⑀R␥, which carry cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). 8 NKmediated lysis of tumor cells or virus-infected cells is mainly mediated by NKp46, NKp30, and NKp44 (collectively referred to as natural cytotoxicity receptors [NCRs]) and by NKG2D. 5,[9][10][11] NKp46 and NKp30 are present on both resting and activated NK cells, whereas NKp44 is expressed only upon NK-cell activation. NKp30 and NKp46 deliver intracellular signals, thanks to their association with CD3 or CD3 plus Fc⑀R␥, respectively, whereas NKp44 associates with the KARAP/DAP12 molecules. 12 Other activating receptors include DNAM-1, 2B4, NTBA, and NKp80. Notably, 2B4, NTBA, and NKp80 are considered coreceptors, as they can significantly increase the NK-cell cytotoxicity against some cellular targets when they are coengaged with NCRs or NKG2D. [13][14][15][16][17] It is evident that the surface expression of activating receptors is crucial for the NK-mediated killing of various target cells. Therefore, it appeared conceivable that immunosuppressive drugs such as glucocorticoids (GCs) could impair the NK-cell function by affecting the surface expression and/or the function of activating NK receptors. In this context, we have recently shown that pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) display a profound down-regulation of most activating NK receptors and coreceptors and an impaired cytolytic activity. This effect appeared to be related to the administration of methylprednisolone (MePDN) to treat graftversus-host disease (GvHD). Indeed, in vitro analysis of NK cells from healthy donors confirmed that MePDN could induce both down-regulation of the NKp30 and NKG2D activating NK receptors and a sharp impairment of NK-cell function. Moreover, in spite of its unaltered surface expression, NKp46 failed to efficiently transduce triggering signals. 18 In this context, however, it should be stressed that NK-cell cytotoxicity is a complex process that requires adhesion to target cells, synapse formation, signal transduction leading to granule polarization, and exocytosis. Accordingly, it is conceivable that MePDN might also interfere with different steps of this process.In previous studies, GCs have been shown to inhibit different T-cell functional activities (including proliferation, cytotoxicity, The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and sole...

IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells

“…IL-15 has been shown to augment intracellular signaling and recruit antiapoptotic proteins, which could support functional durability of NK cells. 35,36 This agrees with studies showing that IL-15-activated human NK cells are functionally resistant to steroid inhibition 37 and sustain their superior in vivo proliferation. 1,35,38 In T cells, IL-15 promotes survival via upregulating Bcl-2 39,40 and antioxidant proteins 41,42 and limiting proapoptotic caspase-3.…”

A novel immunomodulatory mechanism of ribavirin in suppressing natural killer cell function

“…The ligation of NK cell with its target rapidly causes a transient activation of ERK, which apparently control lytic granule movement [31]. Indeed, the activation of the mitogenactivated protein kinase (MAPK) pathways, ERK1/2 and JNK, by activating receptors like NKp46, CD16, 2B4, and NKG2D [15,33] has been reported to play a pivotal role in NK cell cytotoxicity and granule polarization. ERK2 in particular was reported to be the final mediator of perforin and granzyme B granule polarization towards target cells [31].…”

“…For instance, methylprednisolone down-regulated and impaired function of triggering receptors involved in NK cytototoxicity [15,29]. It also inhibited Jak/STAT and ERK1/2 signaling as well as M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 A c c e p t e d M a n u s c r i p …”

“…IL-15Rβ is associated with Janus kinase (Jak)-1 and the γ c is associated with Jak-3, resulting in signal transducer and activator of transcription (STAT)-3 and STAT-5 phosphorylation respectively, following ligation with IL-15 [13]. IL-15 also activates the phosphorylation of STAT-1 [14,15]. In addition to signaling via IL-15/IL-15R, NK cell activation is also tightly regulated by a delicate balance between signaling through inhibitory [killer immunoglobulin-like receptors (KIR), CD94-NK group 2, member A (NKG2A)] and activating receptors [natural cytotoxic receptors (NCRsNKp30, NKp44 and NKp46), NK group 2, member D (NKG2D) and DNAX accessory molecule-1 (DNAM-1)] [10].…”

The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β

“…While Guo et al 2008 [39] revealed that enzastaurin suppressed ERK1/2 and p38 but not JNK phosphorylation in hepatocellular carcinoma, Moreau et al 2007 [40] showed an induction of ERK1/2 phosphorylation by enzastaurin in Waldenström macroglobulinemia. Since ERK1/2 and p38 may play a role in NK cell activation [41,42] we tested by western blot whether enzastaurin treatment has influence on ERK1/2 and p38 activation in primary NK cells and NK-92 cell line.…”