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REVIEW ARTICLE
From the Departments of Internal Medicine and Molecular
Virology, Immunology, and Medical Genetics, Divisions of
Hematology/Oncology and Human Cancer Genetics, and the Comprehensive
Cancer Center, The Ohio State University, Columbus, OH.
Since the cloning of interleukin (IL)-15 six years ago,
there have been numerous studies examining the molecular and cellular biology of this cytokine. IL-15 and IL-2 have similar biologic properties in vitro, consistent with their shared receptor (R) signaling components (IL-2/15R The discovery of IL-15 and its relation to IL-2
Scientists at the Immunex Corporation (Seattle, WA) isolated the 14- to 15-kd protein responsible for the CTLL proliferation within CV-1/EBNA supernatants using anion-exchange and high-pressure liquid chromatography and sequenced the NH2-terminal residues. Degenerate oligonucleotide primers were generated from this partial protein sequence and were used to obtain the full-length simian IL-15 cDNA from a CV-1/EBNA cDNA library. With simian IL-15 cDNA as a probe, the full-length human IL-15 cDNA was cloned from the IMTLH bone marrow stromal cell line.1 The IL-T protein identified by researchers at the National Institutes of Health within HuT-102 supernatants was later cloned and shown to be a chimera composed of the HTLV-1 long terminal repeat (LTR) and human IL-15. The HTLV-1 LTR was fused in frame immediately upstream of IL-15, thereby deleting a portion of its 5' untranslated region (UTR).2-4 Because IL-15 was initially identified through its ability to mimic
IL-2-induced T-cell proliferation, the biochemical and functional
relation between these cytokines was quickly examined. Comparisons of
the primary protein and cDNA sequences of human or simian IL-15 yielded
little primary homology to IL-2; however, computer modeling of IL-15's
secondary structure suggested that IL-15 belonged to the 4 Structure of the genomic locus encoding IL-15 The IL-15 gene spans 34 kb or more, mapping to human chromosome 4q31 and the central region of mouse chromosome 8.10,11 The genomic structure of human IL-15 contains 9 exons (7 coding exons), with a similar intron/exon structure and estimated size between the murine and human IL-15 genes.10,11 More recently, an alternative exon has been described in human12-14 and murine15,16 IL-15, consisting of an additional sequence between exons 4 and 5 that encodes an alternative leader peptide. The structure of the human IL-15 genomic locus is diagramed in Figure 1 and includes the recently described alternative exon (4A).11,12,14 The IL-2 gene is located on human chromosome 4q26-28 and consists of 4 exons and 3 introns.17,18 Of note, the overall intron/exon structure of the portion of the IL-15 gene encoding the mature IL-15 protein (4 exons and 3 introns) is similar to that of the IL-2 gene and other 4 -helix bundle
cytokines.5 However, consistent with other family members,
there is little primary homology between IL-2 and IL-15 at the
nucleotide or protein level (Figure
2).1 Thus, although it is
doubtful that the IL-2 and IL-15 genes have a direct, recent ancestral
relationship, the gene structure of all members of the 4 -helix
bundle cytokine family appears similar.5
IL-15 mRNA isoforms, signal sequences, and intracellular trafficking The originally identified human IL-15 cDNA contains a 5' UTR of at least 316 base pairs (bp), a 486-bp open reading frame, and a 3' UTR of at least 400 bp, encoding a precursor IL-15 with an unusually long 48-amino acid (AA) leader peptide and a 114-AA mature protein.1 Identification of human, simian, and murine IL-15 indicated that IL-15 was conserved between species (97% identity comparing human and simian; 73% identity comparing human with murine).1 An alternative human IL-15 cDNA was identified containing an additional exon.12,13 This variant IL-15 human cDNA contains 119 nucleotides (nt) within intron 4 but lacks exons 1 and 2 of the original cDNA, resulting in a smaller spliced mRNA product (Figure 1).14 However, this exonic sequence encoded 3 premature stop codons and a novel downstream ATG translation start site, resulting ultimately in an IL-15 precursor protein with a 21-AA short signal peptide (SSP), compared with the original 48-AA long signal peptide (LSP). A similar alternative transcript has been described in the mouse.15,16 In human and mouse, both IL-15 isoforms encode an identical mature IL-15 protein, containing differences only within the signal sequence. Regulation of the IL-15 mRNA species expressed may occur through alternative splicing and/or an additional uncharacterized IL-15 promoter driving the expression of the SSP-IL-15.14The 2 IL-15 mRNA isoforms have significant differences in the
N-terminal portions of their leader peptides (Figure 1). Leader peptides determine the intracellular localization and potential secretion of the associated mature protein. Both LSP-IL-15 and SSP-IL-15 appear to have low secretion potential compared with well-secreted cytokines such as IL-2, as replacement of either endogenous IL-15 signal peptide (SP) by CD3313 or
IgV Structure of the mature IL-15 protein The 14- to 15-kd, 114-AA mature IL-15 protein is encoded by exons 5 to 8 of the IL-15 gene (Figure 1).1,10,11 IL-15 contains 2 disulfide bonds at positions C42-C88 and C35-C85 (single-letter amino acid codes), the former being homologous to the C-C within IL-2. There are 2 N-linked glycosylation sites at the C-terminus of the IL-15 protein, at N79 and N112. The mature IL-15 protein has been predicted to have strong helical moments at AAs 1 to 15, 18 to 57, 65 to 78, and 97 to 114, supporting a theoretical model of a 4 -helix bundle
structure (Figure 2).1,23
The IL-15 receptor (R) complex and its relation to the IL-2R complex Three different IL-2R complexes exist: The isolated IL-2R binds
IL-2 with low affinity (Ka approximately 108
M 1) without transducing a signal; the heterodimeric
IL-2R![]() binds IL-2 with intermediate affinity (Ka
approximately 109 M 1) and transduces
intracellular signals; and the heterotrimeric IL-2R![]() ![]() binds IL-2
with high affinity (Ka approximately 1011 M 1) and also signals.18,24,25 The IL-2R ,
also referred to as c, is shared by receptors for IL-2,
IL-4, IL-7, IL-9, and IL-15.26,27 Early experiments using
specific blocking monoclonal antibodies (MoAbs) documented the
participation of the IL-2R and c, but not the
IL-2R , in IL-15 binding and function, suggesting the presence of an
additional subunit for high-affinity IL-15 binding to the IL-15R
complex.3,7,28,29 The murine and human IL-15R subunits
were subsequently cloned and characterized and shown to be highly
homologous to their IL-2R counterparts.29,30 The
full-length human IL-15R is a type-1 transmembrane protein with a
signal peptide of 32 AAs, an extracellular domain of 173 AAs, a
transmembrane domain of 21 AAs, a 37-AA cytoplasmic tail, and multiple
N- or O-linked glycosylation sites.30,31 Comparison of the
IL-2R and the IL-15R revealed the presence of a conserved protein
binding motif (sushi domain or GP-1 motif) and similar intron/exon
structure, placing IL-2R and IL-15R as the founding members of a
new receptor family.29 Through transfection experiments, it was established that the full-length IL-15R alone was sufficient for high-affinity (Ka greater than or equal to
1011 M 1) binding of IL-15, but, similar to
IL-2R , it played no role in signal transduction. This high affinity
of the isolated IL-15R for IL-15 is in stark contrast to the
IL-2R , which has low affinity for IL-2 (Ka approximately
108 M 1) in the absence of the IL-2R![]() .
Thus, the IL-15R binds IL-15 with high affinity, but transduces
signals only in the presence of the IL-2/15R and c
(Figure 2). IL-15, like IL-2, may also bind and signal through the
heterodimeric IL-2/15R![]() c with intermediate affinity
(Ka approximately 109 M 1) in the
absence of IL-15R .28
Eight splicing variants of the hIL-15R The originally identified full-length IL-15R How does IL-15 relate to other cytokines that use the
c receptor, including
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which use additional
subunit(s) for specificity or signaling.34,35 In vivo
experiments engineering mice with targeted disruption of these
cytokines or their specific receptor subunits elegantly demonstrated
that although c is shared, it mediates different
biologic functions when paired with individual cytokines. Comprehensive
comparative reviews of c-binding cytokines have been
provided elsewhere.36-38
Pathways of IL-15 signal transduction Because IL-2 and IL-15 share common signaling components (IL-2/15R![]() c), most evidence to date suggests that the
interaction of IL-15 with its receptor complex in various cell types
leads to a series of signaling events that are similar, if not
identical, to those elicited by IL-2.39 These include
activation of the Janus kinase (Jak)/signal transducer and activator of
transcription (STAT) pathway.40 IL-2/15R is associated
with Jak1 and the c is associated with Jak3, resulting
in STAT3 and STAT5 phosphorylation, respectively, after ligation with
IL-15 (Figure 2).41,42 Additional signaling pathways
through the IL-2/15R complexes include the src-related
tyrosine kinases, induction of Bcl-2, and stimulation of the
Ras/Raf/MAPK pathway that ultimately results in fos/jun activation.43 In neutrophils, IL-15 has been shown to
activate NF- B but not AP-1, whereas IL-15 stimulation of bulk human
peripheral blood lymphocytes activated both transcription
factors.44 However, reports of IL-15- but not
IL-2-induced signals in an IL-15R +IL-2/15R colonic
epithelial cell line leave open the possibility of alternative
IL-15R signaling mechanisms.45 The alternative receptor
system in mast cells (IL-15RX) has been shown to induce phosphorylation
of Jak2 and STAT5,33,46 as well as Tyk2 and STAT6.47
Physiologic expression of IL-15 IL-15 mRNA is produced by multiple tissues (placenta, skeletal muscle, kidney, lung, heart, monocytes/macrophages)1 and numerous cell types through various stimulatory conditions.48-60 The first cell types to be implicated as a functionally relevant source of IL-15 in the context of the immune response were members of the monocyte/macrophage lineage.48,49 Other antigen-presenting cells (APCs), such as blood-derived dendritic cells, have been shown to produce IL-15 mRNA and protein, suggesting a role in the attraction and stimulation of T cells.50,51 IL-15 is also produced by bone marrow (BM) stromal cell lines,1 primary human BM stromal cells,52 thymic epithelium,53 and fetal intestinal epithelium,54 consistent with IL-15's role during hematopoiesis. Epithelial and fibroblast cells from various tissues have been documented to produce IL-15 mRNA and/or protein, including kidney epithelial cell lines,1 epidermal skin cells and keratinocytes,55 fetal skin,56 retinal pigment epithelium,57 and intestinal epithelial cells.58 Other cells producing IL-15 with a less obvious function, and requiring further investigation, include kidney proximal tubule cells59 as well as astrocytes and microglia.60 Although not detected initially,1 T cells were later shown by more sensitive techniques to express IL-15 mRNA.61 Considering the extensive posttranscriptional control of IL-15 now evident (see below), it will be important to document IL-15 protein production, either intracellularly, at the cell surface, or secreted extracellularly, to better understand the true role of IL-15 during normal homeostasis and immune defense.Regulation of IL-15 gene expression IL-15 transcription, translation, and secretion have proved to be regulated through multiple complex mechanisms. This topic has been recently reviewed in depth elsewhere,46,62 and only the major points of interest are summarized here. Although transcriptional control of IL-15 is important,63,64 the principle level of IL-15 regulation appears to be posttranscriptional.Control of transcription.
Both human and murine 5' regulatory regions upstream of exon 1 have
been cloned, sequenced, and analyzed for consensus transcription factor
binding motifs.61,65 These studies revealed some common consensus binding sites within the mouse and human promoter regions, including 348 to 336 relative to the cap site of the
murine IL-15 promoter, following the observation that IRF-1 / mice simultaneously lack inducible IL-15
expression and natural killer (NK) cells.63,64 It remains
unclear what upstream signals are responsible for IRF-induced IL-15
expression during the normal physiologic process of NK cell development
in the BM (discussed below).
Primary regulation of IL-15: translation, intracellular trafficking, and secretion. Three primary checkpoints have been identified that regulate IL-15 mRNA translation into the IL-15 precursor protein: multiple start codons (AUGs) in the 5' UTR, the unusual LSP and SSP, and a negative regulator near the C-terminus of the precursor proteins. The LSP-IL-15 5' UTR is relatively long (more than 316 nt in humans) and contains multiple (12 in humans) AUGs upstream of the actual translation start site that have been shown to dramatically reduce translational efficiency.1,4,66 Bamford et al4 demonstrated that removal of 8 of 10 upstream AUGs in the 5' UTR of the human LSP-IL-15 by fusion with the HTLV-1R region resulted in enhanced IL-15 protein production in the HuT-102 cell line (approximately 5- to 10-fold). However, when the upstream AUGs were circumvented, IL-15 translation and secretion still appeared lower than those of other cytokines, such as IL-2. Tagaya et al14 showed that replacement of endogenous IL-15 signal peptides with the human IL-2 signal peptide resulted in dramatically elevated IL-15 levels detectable in supernatants from COS-7 transfectants. LSP-IL-15 was shown to have a lower translational efficiency than SSP-IL-15 or IL-2SP-IL-15. With the use of IL-15-GFP fusion constructs, it was evident that SSP-IL-15 was restricted to the cytoplasm and nucleus, whereas LSP-IL-15 was detected within the ER/Golgi apparatus. Thus, it appears that SSP-IL-15 is translated efficiently but not secreted, whereas LSP-IL-15 is translated less efficiently but has complex trafficking through the ER/Golgi pathway and is secreted from the cell at low levels.14,21 Similarly, Gaggero et al20 showed that LSP-IL-15 and exogenous IL-15 were detectable in Chinese hamster ovary (CHO) cell endosomes, indicating that rapid uptake by IL-15R-bearing cells may have a regulatory effect on the action of IL-15. The CTLL bioactivity of the LSP-IL-15-GFP construct was significantly higher than that of the LSP-IL-15 without a 3' tag, suggesting that a signal in the carboxyl portion of the mature IL-15 protein results in inefficient secretion, possibly through a retention signal.20 Through the systematic elimination of these 3 checkpoints, that is, removing upstream AUGs, replacing the endogenous human IL-15 leader with that of IL-2, and fusing the C-terminus of the IL-15 mature protein with the FLAG epitope tag, the synthesis of bioactive IL-15 increased 250-fold.67 Such complex and tight control of the IL-15 gene product is unusual for most cytokines characterized thus far and may indicate that IL-15, if overproduced, is somehow dangerous to the host. Transgenic mice that overexpress IL-15 as a result of elimination of posttranscriptional checkpoints recently provided in vivo evidence supporting this hypothesis.68 These mice developed a fatal lymphocytic leukemia following early expansions in NK and CD8+ T cells (see below). Recently, Musso et al69 detected bioactive IL-15 protein constitutively expressed on the surface of human monocyte/macrophage cell lines and primary human monocytes. Cell surface expression was increased upon stimulation with interferon (IFN)- , suggesting a
mechanism by which IL-15 could exert a biologic effect while being
undetectable in culture supernatants. It is unclear whether this
membrane expression of IL-15 depends upon signal peptide expression.
Another recent report demonstrated constitutive IL-15 protein
expression in human PBMCs by Western analysis and flow cytometry, which
was up-regulated by Cryptococcus neoformans, LPS, or
IFN- .70 Further study should reveal the exact cell types, tissue distribution, and functional significance of constitutive cell surface expression of IL-15. IL-15's function in promoting the
survival of IL-15-responsive cell types, such as NK
cells71 and memory T cells,72 may be one
hypothesis explaining the reason for low constitutive protein
expression. Then, in response to an infectious insult, cytoplasmic
protein may be translocated to the cell surface to further stimulate
IL-15R-bearing cells, in combination with additionally induced
monokines such as IL-12.
In other physiologic settings such as NK cell development (discussed
below), it will be interesting to examine BM stromal cells for
constitutive cell-surface expression of IL-15 and to test whether any
signals induce the movement of cytoplasmic IL-15 protein to the cell
surface. In both of these settings, it seems likely that activation of
monocytes/macrophages (and other cells such as dendritic cells and
epithelium) or appropriate stimulation of BM stromal cells could result
in more efficient IL-15 synthesis, translocation, and secretion through
removal of the multiple posttranscriptional control points.
An essential role for IL-15 in NK cell development Two critical features of the mammalian innate immune system are its ability to rapidly limit the spread of infectious pathogens and its ability to prepare the antigen-specific or adaptive immune system to effectively clear the pathogens.73 NK cells74,75 are large granular lymphocytes (LGLs) that demonstrate cytotoxicity against tumor and virally infected cells, produce immunoregulatory cytokines and chemokines, and are an important component of the innate immune defense against viruses, fungi, bacteria, and protozoa.76-80 NK cells also express a number of cell surface receptors that recognize MHC class I ligands and regulate NK cell activation and lysis of target cells,81,82 and are likely to be important for the control of some cancers.83It has long been appreciated that NK cells require the BM
microenvironment for complete maturation, based upon studies examining mice with BM ablation by strontium 89 or
IL-15 differentiates human NK cells in vitro.
First, for IL-15 to be the major physiologic growth factor responsible
for NK cell ontogeny, it must be expressed at the anatomic site of NK
cell differentiation, the BM. In support of this, the human IL-15 cDNA
was first cloned from the IMTLH BM stromal cell line.1
Mrozek et al52 directly demonstrated that primary human BM
stromal cells produced IL-15 at the transcript and protein levels,
while lacking any expression of IL-2. Further, a 3-week culture of
CD34+ hematopoietic progenitor cells (HPCs) supplemented
with rIL-15 induced the differentiation of functional CD56+
NK cells in the absence of stroma or other cytokines. The
CD56+ NK cells generated in these cultures lysed MHC class
I tumor targets, produced cytokine and chemokines upon stimulation, and expressed cytoplasmic CD3- + cells after 10 days, and
cell sorting experiments showed that these
CD34brightIL-2/15R + cells have a 65- to
200-fold higher NK cell precursor frequency compared with freshly
isolated CD34+ HPCs. FL and KL also increased expression of
IL-15R mRNA within CD34+ HPCs measured by reverse
transcriptase polymerase chain reaction (RT-PCR). Thus, human NK cell
development can be divided into an early phase in which an NK
progenitor cell responds to early-acting stromal cell growth factors
(eg, FL or KL) and develops into an NK cell precursor intermediate with
the basic phenotype
CD34brightIL-2/15R +CD56 . This
NK precursor is then responsive to IL-15 for maturation into a
functional CD56+ NK cell (Figure
3).106
It is important to note that the NK cells resulting from adult CD34+ HPCs in stroma-free cultures with IL-15 are CD56+, lyse tumor target cells, and produce immunoregulatory cytokines and chemokines upon stimulation. However, these NK cells have high-density expression of CD56, closely resembling the minor CD56bright NK cell population in peripheral blood, as they have little surface expression of CD16, with most cells expressing C-type lectin CD94/NKG2 NK receptors (NKR) and only small (1% to 8%) percentages of cells expressing killer-cell immunoglobulin-like receptor (KIR).106 This suggests that other soluble or cell-contact signals, perhaps from BM stroma, are required for normal KIR acquisition and other CD56dim NK characteristics, or alternatively the CD56dim NK cell may have a different precursor. To address these issues, further experiments are needed comparing IL-15-based culture systems using various starting HPC populations, with and without autologous BM stroma (or other MHC class I interaction systems). Additional human culture systems have also supported a central role for IL-15 in human NK cell development from various starting progenitor populations, including cord blood CD34+,107,108 adult BM CD34+,108 fetal liver CD34+CD38±,109 and thymocyte T/NK progenitors.110 Beginning with CD56 CD16+ cord blood cells, Gaddy and
Broxmeyer111 have demonstrated that IL-15 induced the
maturation of these cells into highly lytic, phenotypically mature NK
cells. Collectively, these in vitro human culture systems demonstrate a
central role for IL-15 in the later stages of NK cell development from
various adult and fetal progenitors. Further studies are needed to
clarify how IL-15 acts in concert with signals from early-acting growth
factors and stromal cells to facilitate physiologic human NK cell
development and normal NK cell repertoire acquisition. The basic
understanding of how human NK cells develop can also be directly
translated to optimizing the ex vivo112 and in vivo
expansion of this lymphocyte subset for therapeutic intervention.
IL-15 differentiates murine NK cells.
In vitro murine culture systems have also demonstrated a critical role
for IL-15 during NK cell ontogeny. Leclercq et al showed that
bipotential T/NK progenitors113 isolated from the thymus selectively differentiated into NK cells in the presence of
IL-15.53 Addition of high concentrations of IL-15 to
progenitors in fetal thymic organ cultures (FTOCs) blocked TCR and respond to IL-15 for mature NK cell development. In both systems, there is
abnormal NK receptor repertoire development in the presence of IL-15
alone, suggesting that other signals, as discussed earlier, are
required for proper NKR acquisition.
Mice with targeted genetic alterations demonstrate that IL-15 is a
critical NK cell differentiation factor in vivo.
As introduced earlier, the phenotypes of mice with targeted disruption
of IL-2, IL-2R / mice develop into functional NK cells upon
culture in IL-15 or transfer into lethally irradiated wild-type mice,
suggesting that IRF-1 is required for the expression of IL-15 in the BM
microenvironment. Indeed, IRF-1-binding sites have been identified in
the 5' regulatory region of the IL-15 gene, supporting this
hypothesis.63 At present, it is unclear what provides the
endogenous signal to activate IRF-1 within BM stromal cells, which in
turn induces the IL-15 expression important for NK cell development.
Mice with targeted disruption of the Ets-1 transcription factor were
shown to have a selective deficit of NK cells.124
Ets-1 / mice do not appear to have defects in
IL-15R![]() ![]() , IL-15, or IL-2 expression, leaving the precise
mechanism responsible for this NK cell deficiency unknown. Because
Ets-1 is expressed in mature NK cells, it is possible that upstream
IL-15-derived signals may induce Ets-1 that may then orchestrate the
expression of an NK cell genetic program. Further investigation into
the genetic changes at the molecular level during NK cell
differentiation will help to clarify the gene programs activated during
NK cell ontogeny and the transcription factors involved in this process.
Lodolce et al9 recently generated mice with targeted
disruption of the IL-15R , providing direct evidence that the
IL-15/IL-15R![]() ![]() system is critical for murine NK cell
development. These mice contain multiple defects in innate immune
effectors, including an absence of splenic NK cells and NK cytotoxic
activity. Moreover, IL-15 / mice also lack any
phenotypic or functional NK cells in the spleen and liver, a defect
that is reversible upon administration of exogenous IL-15 for 1 week.8 Exogenous IL-15 treatment of normal mice increases
NK cell activity and both the percentage and absolute number of splenic
NK cells.8,125,126 Transgenic mice that overexpress murine
IL-15 have been generated and demonstrate a striking early expansion in
NK cells.68 Thus, in vivo evidence demonstrates that IL-15
is requisite for murine NK cell development, and exogenous IL-15
supports the differentiation of human NK cells in BM culture systems.
These basic observations provide invaluable insight into the critical,
nonredundant role of IL-15 during NK cell development and suggest the
potential utility of IL-15 therapy to expand NK cells in patients.
IL-15 activates NK cell proliferation, cytotoxicity, and cytokine production and regulates NK cell/macrophage interaction NK cells constitutively express cytokine receptors and produce abundant cytokines and chemokines during the early, innate immune response to infection. Such NK cell-derived immunoregulatory factors may be vital in the orchestration of the innate immune response, as well as influence the developing adaptive response.73,78,127 NK cells constitutively express IL-2/15R![]() c, but the lack of abundant IL-2 during the
early innate immune response prompted us to investigate the role of
IL-15 as the more important physiologic ligand for NK cell
proliferation, cytotoxicity, and cytokine production in this setting.
The majority (approximately 90%) of human NK cells have low-density
surface expression of CD56 (CD56dim), express high surface
density of CD16 (Fc RIII), and have a low proliferative capacity.
CD56bright NK cells represent a minor subset (approximately
10%) of human NK cells that are low or negative for CD16 and are
capable of high proliferation.75
NK cell proliferation and cytotoxicity.
IL-15 induced the proliferation of CD56bright NK cells in a
dose-dependent fashion to a similar extent as IL-2, yet required a
nanomolar concentration to activate the IL-2/15R IL-15 costimulates NK cell cytokine and chemokine production and
regulates interactions between macrophages and NK cells.
IL-15 acts in concert with IL-12 to induce the macrophage-activating
factors IFN- , mycobacteria, Toxoplasma
gondii, C neoformans, and Salmonella have been shown to
express IL-15.1,48,49,134,135 In human cocultures of
LPS-stimulated macrophages and NK cells, endogenous IL-15 produced by
the activated macrophages, working in concert with IL-12, was shown to
be critical for optimal IFN- production by human NK
cells.48 Similarly, in vitro culture of LPS-activated
severe combined immunodeficiency (SCID) mouse splenocytes (NK cells and
macrophages) produced abundant IFN- protein, which was abrogated by
blocking the IL-2/15R or neutralizing IL-15.133 In
vivo, preadministration of either an antibody that blocks the
IL-2/15R or a neutralizing anti-IL-15 antiserum to SCID mice
resulted in a significant reduction in serum IFN- measured in vivo 6 hours after an LPS challenge.133 Therefore, in both mice
and humans, activated macrophages and NK cells interact through a
paracrine feedback loop, with macrophages producing monokines (eg,
IL-15 and IL-12) that bind to surface receptors constitutively present
on NK cells, resulting in the production of macrophage-activating
factors (eg, IFN- ). NK cell-derived macrophage-activating factors
in turn feed back upon the macrophages to further augment their
activation (Figure 4). Thus,
macrophage-derived IL-15 contributes with other monokines (especially
IL-12) to the proinflammatory cascade leading to innate immune IFN-
production. Additionally, Ross and Caligiuri130
demonstrated that continuous stimulation of CD56+ NK cells
with IL-15 + IL-12 in vitro results in NK cell apoptosis mediated
through an autocrine TNF- -dependent mechanism, initiated after 24 hours of monokine stimulation. This may represent one means whereby the
innate immune system limits itself after prolonged activation.130
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