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Journal of Leukocyte Biology Volume 57, January 1995 13
Interleukin-2 and human monocyte activationIgor Espinoza-Delgado�’t Maria Carla Bosco� Tiziana Musso,t G. Luca Gusella,Dan L. Longo,5 and Luigi Varesio**Macrophage Cell Biology Section, Laboratory of Experimental Immunology, Biological Response Mod�fiers Program
(BRMP), National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland,’ TMedicine
Branch, Clinical Oncology Program, Division of Cancer Treatment, Bethesda, Maryland,’ tBiological Carcinogenesis
Development Program, Program Resources, Inc/Dyn Corp. FCRDC, Frederick, Maryland; and Office of the Associate
Director, BRMP Division of Cancer Treatment, National Cancer Institute, FCRDC, Frederick, Maryland
INTRODUCTION
Metchnikoff first described mononuclear phagocytic cells at
the end of the last century and proposed their critical in-
volvement in the host immune defense. Since then, an im-
pressive body of literature has documented the involvement
of monocytes in the immune response as immunomodulat-
ing cells [b, 2], antigen-presenting cells [3], and effector cells
[1, 4-7]. Human monocytes can be induced to express new
or augmented biological functions in a process generally
referred to as activation. The expression of the activated
phenotype in monocytes is transient and, in contrast to that
of other immune cells such as lymphocytes or natural killer
(NK) cells, it is not associated with proliferation. Monocyteproliferation, occurring primarily in the bone marrow
[8-to], maintains an adequate supply of circulating mono-
cytes ready to extravasate to the tissues in response to physio-
logical or pathological stimuli. The recognition that prolifer-
ation is not part of the genetic program of monocyte
activation poses interesting questions about the function and
biology of growth factor receptors on these cells. Monocytes
express receptors for a variety of growth factors that are
either monocyte lineage specific, such as the macrophage
colony-stimulating factor (CSF-l) receptor [11, 12]; shared
with other cell lineages, such as the granulocyte-macrophage
CSF (GM-CSF) receptor [13]; or typical of other lineages,such as the interleukin-2 receptor (IL-2R) [14-16]. However,monocytes respond to stimulation by growth factors not with
proliferation but with functional changes. Two remarkable
examples are CSF-1 and IL-2. CSF-1 induces proliferation of
monocyte precursors in the bone marrow [17], but it pro-
motes survival [18], migration [b9], cytokine secretion [20),
and cytotoxic responses [2b] in circulating monocytes. IL-2,
originally described as a T cell growth factor [22], is a power-
ful activator of human monocytes. Fresh human monocytes
respond to IL-2 with microbicidal [23] and tumoricidal ac-
tivities [1, 4-7], cytokine [24-28] and growth factor [29-31]
production, and expression of growth factor receptors [21,
32]. We will discuss the effects of IL-2 on human monocytes,
the differential expression and modulation of the IL-2R
subunits, and their relationship with the responsiveness of
monocytes to IL-2. Finally, we will briefly discuss the regula-
tion of IL-2-induced monocyte activation by inhibitory sig-
nals. IL-2 can also activate murine macrophages. However,
we will limit our discussion to the human monocyte system.
IL-2 EFFECTS ON HUMAN MONOCYTES
The response of monocytes to IL-2 leads to the secretion of
several cytokines including interleukin-1� (IL-b/3) [24,
33-35], tumor necrosis factor � (TNF-cr) [25, 28], inter-
leukin-6 (IL-6) [26], and interleukin-8 (IL-8) [27]. TNF-a
and IL-113 are inflammatory mediators cytotoxic or cytostatic
for tumor cells, whose involvement in the acute-phase re-
sponse and in monocyte antitumor activity has been re-
viewed [36-38]. Monocytes are the predominant source of
IL-6 and IL-8 in peripheral blood [26, 39], although other
cell types contribute to the IL-6 and IL-8 levels [26, 40-42].
IL-8 induces chemotaxis in basophils, neutrophils, and
T lymphocytes [43-47] and is member of the family of
chemoattractant cytokines now called chemokines (for areview see ref. 48). IL-6 is a pleiotropic cytokine whose bio-
logical activities include regulation of the acute-phase
response [37, 49], stimulation of multipotent colony forma-
tion of hematopoietic stem cells [50], induction of immuno-
globulin production [51], and induction of T cell growth and
cytotoxic T lymphocyte differentiation [52, 53]. IL-8 andIL-6 induction by IL-2 occurs at the transcriptional level.
The promoter of both genes contains a consensus sequence
for the nuclear transactivator complex NF-xB [54, 55]. The
observation that IL-2 increases the expression of NF-xB
complexes in the nucleus of monocytes suggests that NF-xB
may be involved in the transcriptional activation of IL-8 andIL-6 genes by IL-2 (T. Musso et al., unpublished observa-
tion). Secretion of IL-6 and IL-8 is a specific response to
IL-2 and not a general response to activating stimuli, be-
cause interferon-’y (IFN-y), which is also a potent monocyte
activator, inhibits rather than induces IL-6 or IL-8 produc-
tion [26, 27]. IL-2 stimulates IL-6 and IL-8 production bothdirectly and indirectly by inducing IL-1$ and TNF-a secre-
tion, which, in turn, stimulates the expression of IL-8 and
IL-6 [26, 56]. The indirect response to IL-2 represents an
amplifying loop that is delayed with respect to direct stimula-
tion and that may be important in allowing prolonged pro-
duction of IL-6 or IL-8 during an inflammatory response.One prominent effect of IL-2 on monocytes is the induc-
tion of cytocidal activity against tumor cells [4, 16, 57, 58],
a function that is often considered the ultimate expression of
the activated phenotype. Cytotoxic monocytes may be im-
portant effector cells against tumors, and their efficacy is cur-
rently being tested in clinical trials of adoptive immunother-
apy in cancer patients [6, 59-61]. Killing of tumor cells by
activated monocytes requires at least 24 h of contact between
Abbreviations: CSF-1, macrophage colony-stimulating factor; GM-CSF,
granulocyte-macrophage colony-stimulating factor; IFN-’y, interferon-7;I L-2R, interleukin-2 receptor; LPS, lipopolysaccharide; NF-x B, nuclear
factor xB; NK, natural killer; TtF-j31, transforming growth factor $1;TNF-cs, tumor necrosis factor a.
Received September 2, 1994; accepted September 2, 1994.
14 Journal of Leukocyte Biology Volume 57, January 1995
effector and target cells and reaches plateau levels after 48 hof interaction [16, 21, 62]. Moreover, the monocyte killing
mechanism differs from that of lymphokine-activated killer
(LAK), NK, or T cells because it is not mediated by lytic
molecules such as performs (I. Espinoza-Delgado et al., un-
published observations). Tumoricidal activity is a direct
response to IL-2 [16] and probably involves several mecha-
nism including cell-cell interaction and the release of secre-
tory products, such as arachidonic acid intermediates, oxy-
gen radicals, and/or TNF-cr and IL-1f� [36].
Monocytes also respond to IL-2 with the expression of
growth factors such as GM-CSF [29] and CSF-l [30, 31] and
growth factor receptor such as CSF-l receptor (CSF-1R). The
high-affinity receptor for CSF-l, encoded by the c-fms proto-
oncogene, is a transmembrane glycoprotein with tyrosine
kinase activity expressed only in monocytic cells and in the
placenta [11, 12]. IL-2 is the only known cytokine to up-
regulate CSF-1R, whereas other monocyte stimuli inhibit its
expression [21]. The up-regulation of CSF-1 receptor by IL-2is of importance for the expression of tumoricidal activity
that is short-lived. In fact, it was shown that CSF-1 prevents
the decay of the tumoricidal state and sustains high levels of
cytotoxic activity without inducing proliferation or increas-
ing the survival of monocytes. CSF-1 was effective in sustain-
ing the cytotoxicity induced by IL-2 but not by IFN-’y, which
did not change the levels of CSF-1R expression [21]. Theseresults suggest potential applications of CSF-1 in monocyte/
macrophage-mediated immunotherapy of cancer. For in-
stance, a phase I study demonstrated that recombinant
CSF-1 can be administered safely to patients with metastatic
cancer at doses that show biological activity [63]. Sequentialtreatment with IL-2 and CSF-1 may be as efficient as con-
tinuous IL-2 in maintaining the cytotoxic activity of mono-
cyte and may reduce the toxic effects associated with long-
term administration of high doses of IL-2 [64-66].
In conclusion, IL-2 is a potent physiologic activator of
monocytes that is fully capable of inducing several cytokines,growth factors, and tumoricidal activity without the need for
second signals.
EXPRESSION AND REGULATION OF IL-2R SUBUNITSIN HUMAN MONOCYTES
The susceptibility of monocytes to activation by IL-2 implies
the presence of functional IL-2 binding structures on their
surface. The IL-2R was initially described on T cells and
later was also found expressed on activated B cells [67-69],
neutrophils [70, 71], eosinophils [72], and monocytes [15, 16,
23, 32, 73]. Over the past several years, our understandingof the IL-2R complex has increased substantially [74, 75].
Initially described in lymphoid cells as a heterodimer of two
chains, IL-2Ra and IL-2R13, with molecular masses of 55
and 70-75 kDa, respectively, the IL-2R complex is now
known to have a third component with a molecular mass of
64 kDa, named IL-2R-y [76, 77]. The cDNA for IL-2R�y was
cloned [78, 79], and transfection experiments have shown
that this subunit is essential for the achievement of full
ligand-binding affinity and receptor-mediated internaliza-
tion [76-78, 80], probably through its direct interaction with
IL-2 [81], and suggested that it may play a critical role in in-
tracellular signal transduction [80, 82].Studies of the composition of the IL-2R expressed on fresh
human monocytes demonstrated the constitutive expression
of IL-2Rj3 and IL-2R”y mRNAs and proteins [16, 32, 83, 84).These structures seem sufficient for the induction of a cyto-
toxic response of fresh monocytes to IL-2, because no co-
stimuli are needed for the activation process [16, 57]. IL-2Rf3chain is critical for IL-2 activation of monocytes because
anti-IL-2Rf3 monoclonal antibodies block the cytotoxic ac-tivity induced by IL-2 [16]. IL-2 stimulation augments the
constitutive levels of expression of IL-2R13 mRNA [32] by in-
creasing the stability of the message without an obvious in-
duction of IL-2Ri3 gene transcription [32]. The increase inIL-2Rf3 mRNA in response to IL-2 may be important in
balancing the loss of receptors that follows the interaction
with the ligand and the subsequent internalization, degrada-
tion, and/or shedding of the complex [85]. Similarly to the
IL-2Rj3 gene, the IL-2R’y gene is transcriptionally active in
resting monocytes, and its transcriptional rate cannot bemodified by IFN-’y or IL-2 [83]. Lack of transcriptional con-
trol could be due to the fact that the promoters of IL-2R’y
and IL-2R� genes lack classic TATA motifs [79, 86], a fea-
ture characteristic of genes that are constitutively expressed.
Furthermore, IL-2Ry and IL-2R(� promoters do not contain
NF-xB or CArG motifs that are present in the IL-2Ra
promoter [84, 87-91] and are associated with its transcrip-
tional activation in monocytes and in the monocytic cell line
U937 (I. Espinoza-Delgado et al., unpublished observa-
tions). The constitutive levels of IL-2R’y mRNA are up-
regulated by IL-2 or IFN-y [83) through stabilization of the
message. The role of IL-2Ry in the monocyte activation
process has not yet been clearly established. About 30 to
40% of fresh monocytes constitutively express IL-2R’y (M.C.
Bosco, unpublished observations), whereas IL-2Rfl is ex-
pressed in more than 90% of fresh monocytes [16]. Binding
experiments with biotinylated IL-2 demonstrated that 30 to
40% of monocytes are able to bind IL-2 [83]. Furthermore,total cellular IL-2R’y protein, measured by Western blotting,
is increased by IL-2 [84] and paralleled by an increase in
IL-2 binding [83]. Therefore it appears that IL-2R’y is a
limiting factor in the extent of IL-2 binding by monocytes
and that the y chain is involved in the formation of a func-
tional IL-2R.The mechanisms regulating IL-2Ra mRNA and protein
expression on monocytes differ substantially from those
demonstrated for IL-2Rj3 and IL-2R7. The a chain is notconstitutively expressed [15, 16, 23, 32, 73, 92, 93], and it is
inducible by IFN-’y [14, 16, 23, 32, 58, 73, 92, 94, 95] or
lipopolysaccharide (LPS) [23, 92, 93], but not by IL-2 [23,
32], and the induction by IFN--y is associated with increased
transcriptional activity [32]. The IL-2Ra promoter contains
an NF-xB motif that is recognized by a p5O/p5Ohomodimer
constitutively present in the nucleus of resting monocytes
and is augmented by IFN-y (I. Espinoza-Delgado et al., un-
published observations). Although there is a clear associa-
tion between the transcriptional activity of IL-2Ra promoter
and expression of p50/p5O homodimer, the role of this NF-
xB complex in IL-2Ra gene expression deserves further in-vestigation.
If IL-2R/3/IL-2Ry complex is sufficient to trigger the acti-
vation of monocytes by IL-2, why is there a separate and
refined mechanism for expressing the IL-2Ra? Functional
studies of the activation of monocytes to express tumoricidal
activity support the hypothesis IL-2Ra is important for theformation of high-affinity IL-2 binding sites. In fact, pre-
treatment of monocytes with low doses of IFN-y or LPS,
sufficient to induce IL-2Ra, rendered monocytes susceptible
to activation by suboptimal doses of IL-2, insufficient by
themselves to induce the activated phenotype [23, 32, 92].
The simplest interpretation of these results is that the con-
comitant expression on the membrane of IL-2Ra, IL-2R�,
and IL-2Ry subunits forms a high-affinity site, more
efficient than the heterodimer IL-2R13/IL-2R’y in respond-
Espinoza-Delgado ci aL Interleukin-2 and human monocyte activation
ing to IL-2. IL-2Ra may function as an on-off switch thatdetermines whether monocytes will respond to the low con-centration of IL-2 that may be found in vivo in the monocytemicroenvironments. Monocytes and alveolar macrophages
from patients with tuberculosis, sarcoidosis, and AIDS, but
not their normal counterparts, express IL-2Ra [96-98] in-
dicating that IL-2Ra expression occurs in vivo during aninflammatory response, as suggested by the in vitro studies.
Overall, a relevant and critical feature of IL-2R expressionon monocytes is that the three subunits are independentlyexpressed and differentially regulated with respect to the in-ducing cytokine and mechanism of control of gene expres-sion (Table 1). One reason for such a complex pattern ofregulation could be to control the reactivity of monocytes tolow levels of IL-2 that can be found in the monocyte micro-environments. A second reason is suggested by the findingthat IL-2Ry chain participates in the formation of the recep-tor for other cytokines including IL-4 and IL-7 [99-102] andtherefore the modulation of IL-2R’y expression may affectthe response of monocytes to other cytokines.
INHIBITORY CIRCUITS REGULATING THEACTIVATION OF MONOCYTES BY IL-2
Control of monocyte function is achieved through a balance
of inhibitory and activating signals that dictate the resultingphenotype. Monokines induced by IL-2, such as IL-I, IL-6,IL-8, and TNF, can have deleterious consequences in case ofcontinued or excessive secretion and inhibitory factors ornegative regulatory mechanisms should exist to preventprolonged activation beyond what is appropriate to the ini-tial stimulus. Indeed, the existence of inhibitory circuits con-trolling the response to IL-2 has been demonstrated [26, 27,103] and IFN-y, transforming growth factor j3� (‘]DF-�1),and IL-4 are among the cytokines known to inhibit mono-cyte activation by IL-2.
The inhibitory activity that IFN--y exerts on monocytes is
intriguing, as IFN--y is also a powerful monocyte activator
[4, 5, 21, 104, 105], and its action appears to be restricted tothe expression of selected genes. One example is the tran-
scriptional inhibition of IL-8 production by IL-2-stimulated
monocytes [27]. The mechanisms mediating the inhibitory
effects of IFN-�y are unknown. However, because IFN-y in-
duces the formation of functional high-affinity IL-2Rs on
monocytes, its inhibitory effects on IL-2-activated mono-cytes are probably exerted at a postreceptor level.
TGF-�31 is a 25-kDa polypeptide growth factor producedby transformed cells as well as normal cells, including plate-lets, activated T cells, B cells, macrophages, and monocytes
TABLE 1. IL- 2R Expressi on and Regulation
Subunit
Constitutively
expressed
Augmentation Inhibition
Stimulus
Regulatory
mechanisms Stimulus
IL-2Ra No IFN-��
LPS
T
ND
IL�4b
IL-2R�3 Yes IL-2 PT ND’
IL.2R’y Yes IL-2
IFN-�’
PT
PT
TGF-$
�T, transcriptional; PT, postiranscriptional.
6Murine macrophages.
‘ND, not determined.
[106-108]. ltF-13 is a powerful chemotactic factor for mono-
cytes and plays an important role in wound healing andinflammation [109, 110]. On the other hand, TGF-(3 sup-presses the activity of several immune effector cell popula-tions including T, B, and large granular lymphocytes [107,111, 112], and acts as a monocyte/macrophage deactivatingfactor by decreasing hydrogen peroxide production [113] andTNF-tx production [114]. Furthermore, �TGF-131 selectivelyinhibits IL-2- but not IFN--y-induced tumoricidal activityin human monocytes [103]. The inhibitory effects of TGF-/31
on IL-2-activated monocytes are not limited to the tumorici-dal activity but include the production of IL-6 [26, 115]. Themultiplicity of the IL-2-induced responses inhibited by TGF-f3� suggests that IL-2R expression could be a target ofTGF-f35. In fact, it was found that TGF-131 decreases IL-2RymRNA and protein expression on monocytes [84, 103]. Thiseffect is selective because TGF-fl1 not only did not inhibit butincreased IL-2-induced IL-2R�9 mRNA expression. Thedown-regulation of IL-2R’y expression could be responsiblefor the inhibitory effects of 1’tF-�1 on monocyte activation.
IL-4 is a 20-kDa glycoprotein produced by activated Th2cells [116]. Originally described as a B cell growth factor[117], it has been shown to have a dual biologic effect onmononuclear phagocytes. IL-4 can stimulate monocyte func-tions. For instance, IL-4 induces expression of major histo-compatibility complex class II [118] and CD23 [119] andproduction of CSF-l [120]. However, IL-4 can also inhibitmonocytes and can decrease cytokine secretion [121], hydro-gen peroxide production [122], indoleamine 2,3-dioxygenaseexpression [123, 124], and cytotoxic activity [125]. Moreover,IL-4 inhibits both the costimulatory activity of IL-2 on IFN-y-treated murine macrophages in the induction of tumorici-dal activity [126] and the ability of murine macrophages tosynthesize TNF-a in response to IL-2 [127]. There is little in-formation on the effects of IL-4 on IL-2-activated humanmonocytes. We have found that IL-4 inhibits IL-2- but notIFN--y-induced tumoricidal activity (I. Espinoza-Delgado et
al., unpublished observations). Because IL-4 and IL-2 sharethe IL-2Ry chain, they may compete with each other forbinding to this receptor. The relative concentrations of thetwo cytokines in the environment may determine the kind ofresponse elicited in monocytes. IL-4 has been shown to en-hance apoptosis in monocytes stimulated with IL-i or LPS[128]. It is possible that a similar mechanism is induced byIL-4 in IL-2-activated monocytes, explaining the inhibitoryeffects of IL-4 on IL-2-treated human monocytes.
In summary, IFN-’y, TGF-f�1, and IL-4 can down-modulate the response of human monocytes to IL-2. Thiscontrol is exerted at different levels and degrees dependingon the function in consideration. Understanding the inhibi-
tory network that controls the response of monocytes to IL-2
may be critical in identifying the mechanisms of action of
IL-2.
SUMMARY AND CONCLUSIONS
The recognition of the monocyte/macrophage-activating
properties of IL-2 has broadened our image of the biological
effects of this lymphokine from those of a T cell growth factor
to those of a molecule with pleiotropic effects. The detailed
analysis of the mechanisms of action of IL-2 including its
biological effects on different cell types and the regulation of
its receptors has increased dramatically the spectrum of the
biological responses that can be modified by IL-2. The regu-lation of the expression of the IL-2 receptor .�ubunits differsin terms of response to extracellular stimuli and intracellular
16 Journal of Leukocyte Biology Volume 57, January 1995
control, suggesting that the response to IL-2 will vary de-
pending on the nature and extent of environmental stimula-
tion. Furthermore, the fact that the IL-2R’y chain can be
part of the receptor for IL-4, IL-7, and perhaps other cyto-
kines indicates that IL-2 may modulate the response of
monocytes simply by binding or releasing the IL-2R’y chain
and thus modulating the responsiveness to IL-4 or IL-7.
Conversely, the extent of utilization of IL-2Ry chain by vari-
ous cytokines may dictate the monocytic response to IL-2. In
fact, the availability of IL-2R’y chain seems to be the limiting
factor in the response of monocytes to IL-2.Modulation of cytokine receptors is an integral part of the
control of the IL-2 response. The induction of CSF-1 recep-
tor by IL-2 and the positive effect of CSF-1 on the duration
of the cytotoxic response in IL-2-stimulated monocytes are
an interesting example of a synergistic interaction of poten-
tial physiological relevance. The response of monocytes to
IL-2 can also be modulated by inhibitory circuits, such as
those involving TGF-�31, IFN-� and IL-4. However, IFN--y
and IL-4 can also activate monocytes and the timing andrelative concentrations of the various cytokines may be criti-
cal variables in determining the ultimate monocyte
phenotype.
These studies have given us a glimpse of a very complex
picture composed of multiple backgrounds and several
players. However, the present information is not sufficient tomake meaningful predictions of the resulting monocyte
phenotype in an inflammatory reaction in which multiple
cytokines are involved. It will be important to determine ex-
perimentally the relevance of each variable in the activation
of monocytes in vivo and at the same time to develop com-
prehensive theoretical models to organize the existing infor-
mation into propositions and hypotheses useful for predict-ing and focusing the investigation of the phenotype ofmononuclear phagocytes in pathological situations. With
sufficient understanding, it may be possible to inhibit mono-
cytes when their function is contributory to a pathological
state and stimulate them when their function might eradi-cate a pathological state. The central role of monocytes in
medicine that was foreseen for them by George Bernard
Shaw in “The Doctor’s Dilemma” early in the twentieth cen-
tury has certainly not come to pass. However, we may soon
have enough information to offer monocytes a screen test for
that role.
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