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and functions
Kate Schroder,*, Paul J. Hertzog,, Timothy Ravasi,*, and David A. Hume*,,1
*Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, Australia; CRC for Chronic
Inflammatory Diseases, Parkville, Victoria, Australia; and Molecular Genetics Group, Institute of Reproduction
and Development, Monash Medical Centre, Monash University, Clayton, Victoria, Australia
Abstract: Interferon- (IFN-) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant
genes. This article reviews the current understanding of IFN- ligand, receptor, signal transduction,
and cellular effects with a focus on macrophage
responses and to a lesser extent, responses from
other cell types that influence macrophage function during infection. The current model for IFN-
signal transduction is discussed, as well as signal
regulation and factors conferring signal specificity.
Cellular effects of IFN- are described, including
up-regulation of pathogen recognition, antigen
processing and presentation, the antiviral state,
inhibition of cellular proliferation and effects on
apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis
factor-, interleukin-4, type I IFNs, and lipopolysaccharide are discussed. J. Leukoc. Biol. 75:
163189; 2004.
Key Words: macrophage cytokine lipopolysaccharide Toll-like
receptor inflammation
INTRODUCTION
This review focuses on the interplay between interferon-
(IFN-) and macrophages in inflammation and acquired immunity during infection. Macrophages are extremely versatile
cells involved in a number of complex functions in disease and
health. A pathogen encounters macrophages soon after host
entry, and the result of these encounters is fundamental to the
hosts ability to mount an effective immune response. Macrophage activation, broadly defined as acquisition of competence to execute a complex function [1], is among the first
actions to occur in innate immunity to potential pathogens. In
most situations, macrophages are activated to acquire microbicidal effector functions and secrete proinflammatory cytokines, resulting in inflammation and recruitment of immune
cells and subsequent elimination of the microbe by phagocytosis or release of toxic metabolites.
THE IFNs
The IFNs were originally discovered as agents that interfere
with viral replication [7]. Initially, they were classified by the
secreting cell type but are now classified into type I and type
II according to receptor specificity and sequence homology.
The type I IFNs are comprised of multiple IFN- subtypes
(14 20, depending on species), IFN-, IFN-, and IFN-, all
of which are structurally related and bind to a common heterodimeric receptor (IFNAR, comprised of IFNAR1 and
IFNAR2 chains). Although type I IFNs are secreted at low
levels by almost all cell types, hematopoietic cells are the
major producers of IFN- and IFN-, whereas fibroblasts are
a major cellular source of IFN- [8]. IFN- is also produced by
macrophages under appropriate stimulus (discussed later). Viral infection is the classic stimulus for IFN- and IFN-
expression [8, 9]. Secretion of IFN- has only been reported in
ruminants [10].
IFN- is the sole type II IFN. It is structurally unrelated to
type I IFNs, binds to a different receptor, and is encoded by a
separate chromosomal locus. Initially, it was believed that
CD4 T helper cell type 1 (Th1) lymphocytes, CD8 cytotoxic lymphocytes, and NK cells exclusively produced IFN-
[8, 11]. However, there is now evidence that other cells, such
Correspondence: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane 4072, Australia. E-mail: D.Hume@imb.uq.edu.au
Received June 2, 2003; revised July 25, 2003; accepted July 27, 2003; doi:
10.1189/jlb.0603252.
may induce the apoptotic program [35, 38, 39]. This mechanism may aid in the Th2-to-Th1 phenotype switch apparent
when CD4 cells are treated with IFN-: the Th2 population
decreases as a result of growth-inhibitory and proapoptotic
effects of IFN-, and the Th1 population continues to proliferate as a result of blockade of IFN- function. As a consequence, IFN- signaling causes IFNGR2 down-regulation and
switching to a Th1 phenotype as a T cell population but not at
a single-cell level [37].
Both IFNGR chains lack intrinsic kinase/phosphatase activity and so must associate with signaling machinery for signal
transduction. The IFNGR1 intracellular domain contains binding motifs for the Janus tyrosine kinase (Jak)1 and the latent
cytosolic factor, signal transducer and activator of transcription
(Stat)1. In humans, the Jak1-binding motif LPKS is a membrane-proximal sequence located at residues 266 269 [40
42]. The human Stat1-binding site YDKPH is positioned at
residues 440 444 [43]. This motif contains an essential Y440
phosphorylation site that is phosphorylated during signal transduction to allow Stat1 recruitment to the receptor [42 44].
Residues 441DKPH444 are responsible for the binding specificity of IFNGR1 and Stat1 [41, 43, 44]. The Jak1- and Stat1binding motifs are required for receptor phosphorylation, signal transduction, and induction of biological response. Receptor-ligand internalization is mediated by an isoleucine-leucine
sequence at residues 270 and 271 of the mature IFNGR1 chain
in humans. Mutant receptors with deletion or substitution of
this sequence cannot internalize ligand, although signal transduction is not affected [42, 45].
The intracellular region of IFNGR2 contains a noncontiguous binding motif for recruitment of Jak2 kinase for participation in signal transduction. In humans, these sites are
263
PPSIP267 and 270IEEYL274 [46, 47]. The IFNGR2 chain is
not tyrosine phosphorylated during signal transduction [46].
Cross-linking experiments with labeled human IFN- demonstrated that IFN- only associates with IFNGR2 when the
IFNGR1 chain is present, indicating that the primary interaction between the IFNGR2 chain and the IFN-:IFNGR1 complex is found between IFNGR1 and IFNGR2, although it is
likely that IFNGR2 also interacts weakly with the ligand [46,
48].
IFN-:IFNGR1 and IFNGR1:IFNGR2 interactions are species-specific. A number of studies with chimeric receptors in
which the intracellular, transmembrane, or extracellular domains were swapped between the human and murine IFNGR
chains showed that species specificity in interactions of the
ligand:receptor complex is restricted to the receptor extracellular domains [49 53].
Some viruses (e.g., vaccinia virus, Theilers murine encephalomyelitis virus, and lymphocytic choriomeningitis virus) appear to require both type I and II IFN pathways, whereas
viruses such as Semliki forest virus and vesicular stomatitis
virus require a predominantly type I IFN response for efficient
clearing [60]. These observations have prompted the suggestion that the two IFN systems may have evolved to complement
each other in overlapping but nonredundant activities to defend against a broad spectrum of pathogens [60, 61]. Historically, the type I IFNs were considered to be primarily antiviral
agents with limited immunomodulatory activity, whereas IFN-
was considered to be primarily an immunomodulator with
limited antiviral activity [8]. It is now apparent that both types
of IFN possess antiviral and immunomodulatory activities to
some degree [62]. The antiviral activity of both types of IFNs is
often important in the early stages of viral infection, but their
immunomodulatory activities become important in later stages
of infection when the adaptive immune response becomes
critical [60].
Patients with inactivating mutations of the human IFNGR1
or IFNGR2 chains show clinical presentation similar to the
mouse models. Human loss-of-function mutations in the
IFNGR1 or IFNGR2 chain are closely associated with severe
susceptibility to poorly virulent mycobacteria, often presenting
as early onset bacillus Calmette-Guerin infection and fatality
in childhood [6371]. Partial deficiency of either chain gives a
milder phenotype and a much better prognosis [63 65]. Loss of
functional IFNGR1 appears to be associated only with increased susceptibility to infection with some viruses and intracellular bacteria; increased susceptibility to other common
bacterial and fungi pathogens have not been reported [72].
In addition to recurrent infection, infants with deficient
production of IFN- exhibited decreased neutrophil mobility
and NK cell activity, highlighting the importance of IFN- in
the inflammatory response and immunoregulation [73]. It is
interesting that natural IFN- polymorphisms have been correlated with increased longevity [74]. It has been proposed that
a slightly dampened inflammatory status caused by an IFN-
polymorphism, while not enough to significantly impact on the
individuals ability to clear infection, may prevent or defer
inflammation-related diseases such as cardiovascular disease,
neurodegeneration, osteoarthritis, osteoporosis, and diabetes
[74].
Aside from functions in host defense, IFN- may also contribute to autoimmune pathology. Although IFN- production
was shown to be disease-limiting in autoimmune models such
as murine experimental allergic encephalomyelitis (EAE) [75,
76], it may contribute to autoimmune nephritis [77, 78]. In
humans, IFN- is implicated in pathology of diseases such as
systemic lupus erythematosus [79, 80], multiple sclerosis [81],
and insulin-dependent diabetes mellitus [82 84].
IFN- function is significant in tumor surveillance. IFNGR1
knockout (KO) mice, cells with dominant-negative IFNGR1
mutations, and cells treated with IFN--neutralizing antibodies
display compromised tumor rejection [85 87]. IFN- protects
against tumor development and directs the immunogenic phenotype of tumors that arise in an immunocompetent host (the
cancer immunoediting concept; reviewed in refs. [88, 89]).
SIGNAL TRANSDUCTION
IFN- primarily signals through the Jak-Stat pathway, a pathway used by over 50 cytokines, growth factors, and hormones to
affect gene regulation [90]. Jak-Stat signaling involves sequential receptor recruitment and activation of members of the
Janus family of kinases (Jaks: Jaks 13 and Tyk2) and the Stats
(Stats 1 6, including Stat5a and Stat5b) to control transcription of target genes via specific response elements. As this
signaling mechanism is a recurring theme amongst members of
the cytokine receptor superfamily, IFN--induced Jak-Stat signaling has emerged as the global paradigm for class II cytokine
receptor signal transduction.
The IFNGR1 and IFNGR2 subunits of the IFN- receptor
were thought not to strongly associate with each other in the
absence of ligand [13, 40, 47, 91, 92], but new techniques
allowing the study of receptor chain interactions in intact cells
have shown the receptor complex is assembled before ligand
binding [93]. Upon ligand binding, the intracellular domains of
the receptor chains open out to allow association of downstream
signaling components. Biologically active IFN- is a noncovalent homodimer formed by the self-association of two mature
polypeptides in an antiparallel orientation [94, 95] and thus
binds IFNGR1 in 2:2 binding stoichiometry [47, 9597]. Ligand binding induces Jak2 autophosphorylation and activation,
which allows Jak1 transphosphorylation by Jak2 (Fig. 1) [98].
The activated Jak1 phosphorylates functionally critical tyrosines on residue 440 of each IFNGR1 chain to form two
adjacent docking sites for the SH2 domains of latent Stat1 [41,
99 101]. The receptor-recruited Stat1 pair is phosphorylated
near the C terminus at Y701, probably by Jak2 [98]. Phosphorylation induces dissociation of a Stat1 homodimer (also
known as -IFN activation factor) from the receptor [100]. The
four critical tyrosines (contained by Jak1, Jak2, IFNGR1, and
Stat1) are phosphorylated within 1 min of IFN- treatment [41,
99].
The dissociated Stat1 homodimer enters the nucleus and
binds to promoter elements to initiate or suppress transcription
of IFN--regulated genes (reviewed in refs. [102104]). Stat1
homodimers bind DNA at GAS elements of consensus sequence TTCN(2-4)GAA [105]. The key function of Stat1 in
mediating IFN- signal transduction is indicated by the phenotype of Stat1/ mice, which largely phenocopy IFNGR1/
mice during IFN- stimulation [106].
The first wave of IFN--induced transcription occurs within
1530 min of IFN- treatment [107]. Many of the induced
genes are in fact transcription factors (for example, IRF-1),
which are activated by IFN- and are able to further drive
regulation of the next wave of transcription. Transcription of
many IFN--responsive genes is controlled by a GAS element
or an ISRE [108].
Stat1
The crystal structure for tyrosine phosphorylated Stat1 bound
to DNA has been determined [109]. The structure verified that
the SH2 domain necessary for dimerization is also involved in
ST
AT
STA
1
T1
Cytosol
JAK2
JAK1
JAK1
JAK2
JAK2
JAK1
JAK1
JAK2
IFN
STAT1
STAT1
IRF-9
STAT2
STAT1
STA
T1
STA
T1
IRF-1
IRF-1
IRF-9
eg. ICAM-1
MIG
eg. IRF-2
iNOS
IFN
GAS
IFN-regulated gene
ISRE
IFN-regulated gene
STAT1
STAT1
IRF-1
P
IRF-E/GAS/IRF-E
GAS
IRF-1
Stat1
ST
AT
1
STAT1
STAT1
Nucleus
IRF-1
Fig. 1. The current paradigm for IFN- signal transduction. Ligand binding causes a conformational change in the IFN-R (IFNGR1, yellow; IFNGR2, green),
such that the inactive Jak2 kinase undergoes autophosphorylation and activation, which in turn allows Jak1 transphosphorylation by Jak2. The activated Jak1
phosphorylates functionally critical tyrosines on residue 440 of each IFNGR1 chain to form two adjacent docking sites for the Src homology (SH)2 domains of latent
Stat1. The receptor-recruited Stat1 pair is phosphorylated near the C terminus at Y701. Phosphorylation induces dissociation of a Stat1 homodimer from the
receptor. To a lesser extent, IFN- signaling also produces Stat1:Stat1:IFN regulatory factor (IRF)-9 and Stat1:Stat2:IRF-9 [IFN-stimulated gene factor 3 (ISGF3)]
complexes. Stat1 homodimers travel to the nucleus and bind to promoter IFN--activation site (GAS) elements to initiate/suppress transcription of IFN--regulated
genes. Many of IFN--regulated genes are in fact transcription factors (e.g., IRF-1), which are activated by IFN- and are able to drive regulation of the next wave
of transcription (e.g., induction of IFN-). Stat1:Stat1:IRF-9 heterodimers, ISGF3, and IRF-1 are able to bind to IFN-stimulated response element (ISRE) promoter
regions in target genes to regulate transcription. IRF-1 is also able to promote transcription of Stat1 through an unusual ISRE site (IRF-E/GAS/IRF-E). Signaling
molecules activated by IFN- are depicted in red text. ICAM-1, Intercellular adhesion molecule-1; MIG, monokine induced by IFN-; iNOS, inducible nitric oxide
synthase.
IRF-1
The IRF gene family is intimately involved in mediating the
type I and II IFN signal cascades. Members of the IRF family
share similar structure, including an amino-terminal DNAbinding domain containing multiple tryptophan residues and a
carboxy-terminal transcriptional activation or repression domain (reviewed in ref. [157]). IRF-1, IRF-2, and IRF-9 (p48,
ISGF3-) all participate in IFN- signaling. Basal IRF-1 expression has functions in constitutive gene expression [134],
but Stat1 and nuclear factor (NF)-B interaction with promoter
elements dramatically increases IRF-1 transcription [158
160]. IRF-1 expression is up-regulated in response to types I
and II IFN, virus, or cytokines. IRF-1 transcriptional regulatory activity is regulated independently in response to IFN-,
virus, and dsRNA [161]. The physiological relevance of IRF-1
function in transcriptional control of IFN--regulated genes is
highlighted by IRF-1 KO mice, in which many genes are
submaximally induced by IFN- when compared with their WT
littermates [162, 163]. IRF-1 functions are not limited to IFN-
signaling; IFN--independent activities in viral/bacterial infection, lymphocyte development, regulation of cell cycle,
growth inhibition, apoptosis and tumor suppression have been
reported [107, 123, 135, 159, 164 168].
IRF-1 drives inducible expression of many target genes
through interaction with the IRF-E site, consensus G(A)AAA
G T
/C /CGAAAG/CT/C [102, 164]. This specificity overlaps with
the ISRE consensus site A/GNGAAANNGAAACT, recognized
by ISGF3, which is induced by type I IFN and to a lesser
extent, type II IFN [102]. In this way, IRF-1 is able to induce
a subset of the full spectrum of IFN-inducible genes. IRF-2
also binds to the IRF-E site and largely functions to repress
transcription of IRF-1-inducible genes through its transcriptional repressor domain [102, 159].
172]. In some cell types, IFN- signaling may induce degradation of the internalized receptor, thereby down-regulating
IFNGR1 surface expression [45]. This may be a mechanism by
which these cells can prevent overstimulation of the pathway
through cellular desensitization. Such a mechanism may also
allow differential regulation of IFN--induced responses in
different cell types [37].
One of the most inducible targets of IFN- is a specific
feedback inhibitor, SOCS-1, which associates with Jak1/2,
interfering with tyrosine kinase activity and inhibiting downstream IFN- signaling [173177]. SOCS-1 may also promote
degradation of signaling machinery by binding to and targeting
signaling molecules for the ubiquitin-proteasome pathway
[178]. Overexpression of SOCS-1 in cells in vitro or in transgenic mice causes loss of responsiveness to IFN- [176, 179].
Conversely, SOCS-1/ mice are hyper-responsive to microbial infection, exhibit enhanced macrophage cytocidal activity,
and die of IFN--dependent, multisystem inflammatory tissue
destruction in the absence of infection [180, 181]. This indicates that IFN- is normally present and performs important
functions in vivo, even in the absence of infection. Another
SOCS protein, SOCS-3, is also induced by IFN- and negatively regulates IFN- signaling, although perhaps less effectively than SOCS-1 [182].
Aside from SOCS protein function, IFN- signal downregulation can occur by receptor and Jak dephosphorylation by
the PTPs Shp1 and Shp2 [183187]. Shp2 null cells exhibit
elevated tyrosine phosphorylation and DNA-binding ability of
Stat1 and show enhanced suppression of cell growth with
IFN- treatment [184]. Shp1 KO mice (motheaten mice, me/
me) die from a condition caused by dysregulation of a large
number of cytokines, possibly including IFN- [188].
Stat1 phosphorylation may also be controlled by nuclear
dephosphorylation. Stat1 homodimers enter the nucleus and
are actively retained by a mechanism dependent on the kinase
function of Jak1 [189]. McBride et al. [137] proposed a model
in which nuclear export is mediated by a leucine-rich nuclear
export signal (NES) at residues 197205, which is hidden
when Stat1 is bound to DNA. Stat1 dephosphorylation by a
nuclear protein tyrosine phosphate (PTP) allows the release of
DNA and subsequent recognition of the NES by chromosome
region maintenance/exportin 1 (CRM1), an export receptor for
NES-containing proteins [190, 191]. CRM1 then mediates
Stat1 translocation through the nuclear pore in a Ran-GTPasedependent manner. This model is supported by work from other
groups, demonstrating Stat1 tyrosine dephosphorylation in the
nucleus and subsequent recycling of inactive Stat1 to the
cytoplasm, and is consistent with the crystal structure of Stat1
bound to DNA [137, 189, 192, 193].
Signaling specificity
The many cytokines that use Jak-Stat signaling direct transcription through specific but not necessarily unique combinations of Jaks and Stats. This raises the question of how signal
specificity is maintained when many cytokines use the same
signaling machinery.
Evidence for a devoted role of Jaks in signal transduction of
specific cytokines is controversial. Mutant cell lines lacking
Jak1 or Jak2 have demonstrated deficiency in types I and II
http://www.jleukbio.org
Receptor
expression level
SOCS-3
SOCS-1
PTPs/SOCS limit
receptor and Jak
phosphorylation
STAT1
STAT1
STA
T1
IRF-9
STAT2
STAT1
STA
T1
STA
T1
IRF-1
STA
T1
Cytosol
SHP-2
ST
AT
STA
1
T1
JAK2
JAK1
JAK1
JAK2
JAK2
JAK1
JAK1
JAK2
IFN
IRF-1
IRF-9
Nucleus
STAT1
Nuclear PTPs
dephosphorylate
Stat1 causing
inactivation and
nuclear export
STAT1
STA
T1
STA
T1
PTP
GAS
IFN-regulated gene
eg.
ISRE
IRF-1
IRF-2
IFN-regulated gene
Transcriptional
repression by IRF-2
competition for
ISRE/IRF-E sites
Fig. 2. Negative regulation of IFN- signaling. A number of factors limit the extent and duration of IFN- signal transduction. Receptor IFNGR2 (green)
expression is tightly regulated in some cell types, whereas IFNGR1 (yellow) surface concentration may be regulated by the extent of recycling following
receptor:ligand internalization. Protein tyrosine phosphatases (PTPs), such as SH2-containing tyrosine phosphatase-2 (Shp2), dephosphorylate Jak1, Jak2, and
IFNGR1, and suppressors of cytokine signaling-1 (SOCS-1) and SOCS-3 interfere with Jak activity to turn off signaling after ligand binding. Stat1 activation is
down-regulated by Stat1 dephosphorylation in the nucleus. IRF-2 antagonizes transcriptional activation of many (IRF-1-inducible) genes containing ISRE or IRF-E
promoter elements by competing for binding sites without promoting gene expression. Signaling molecules activated by IFN- are depicted in red text.
TABLE 1.
PA28, PA28
TAP-1, TAP-2
2-microglobulin
Tapasin
Function
Refs.
[210216]
[4, 224231]
[4, 233]
DMA, DMB
Cathepsins B, H, L
CIITA
Function
Refs.
Constituents of the heterodimeric MHC II. MHC II displays foreign and selfpeptides on the cell surface for immune surveillance by CD4 T cells. The
MHC II and chains are encoded by the class II MHC locus.
The invariant (Ii) chain is a transmembrane chaperone, which traffics MHC II
from the ER to the MHC II endosomal compartment (MIIC). An Ii-derived
peptide, CLIP (class II-associated invariant chain peptide), binds to the
MHC II peptide-binding groove to prevent inappropriate peptide binding.
The DMA:DMB dimer forms DM, a class II-like heterodimeric protein resident
in the MIIC. DM functions to remove CLIP from the peptide-binding cleft of
MHC II so that it is accessible for peptide loading. DM is encoded by the
class II MHC locus.
Lysosomal proteases implicated in peptide production for class II MHC loading.
Class II transactivator (CIITA) is a transactivator with no DNA-binding motif. It
is the limiting component of a complex that induces transcription of key
genes involved in class II MHC induction, including constituents of the class
II MHC complex, the Ii chain, and DM.
[234237]
Function
Refs.
[154, 242247]
[237239]
[235, 237]
[240, 241]
[234]
Antiviral Effect
Gene/protein up-regulated
by IFN-
PKR
ADAR
GBP1, GBP2
[248]
171
TABLE 1.
(Continued)
Antiproliferative Effect
Gene/protein up-regulated
by IFN-
PKR
p21, p27
Rb
p202
Mad1
Function
Refs.
[154, 242247]
[251]
Function
Refs.
[263]
[264]
[154]
[251]
[265]
[259]
Function
Refs.
[252]
[253256]
[257]
[155, 258]
[259262]
Apoptotic Effect
Gene/protein up-regulated
by IFN-
IRF-1
Caspase 1 (IL-1-converting
enzyme)
PKR
DAPs
Cathepsin D
Fas/Fas ligand
TNF- receptor
[267269]
[270272]
[273276]
[277]
[278, 279]
[280]
Argininosuccinate synthetase
GTP-cyclohydroxylase I
172
Function
Refs.
The NOS enzymes (NOS1, iNOS, NOS3) catalyze the reduced nictonimide
adenine dinucleotide phosphate (NADPH)-dependent conversion of L-arginine
to L-citrulline, forming NO as a by-product. Of these, iNOS is the only isoform
inducible by cytokine and/or microbial stimulus.
Argininosuccinate synthetase produces the L-arginine substrate required for the
NO-liberating reaction catalyzed by iNOS.
Guanosine 5-triphosphate (GTP)-cyclohydroxylase I supplies the
tetrahydrobiopterin cofactor required for NO production by iNOS.
[281]
[282284]
[285, 286]
http://www.jleukbio.org
TABLE 1.
(Continued)
gp91
gp67phox
Function
Refs.
phox
phox
gp91
is a subunit of the NADPH oxidase, which associates with gp22 ,
gp47phox, and gp67phox to form the active complex capable of the generation
of ROS during the respiratory burst.
gp67phox is a subunit of the NADPH oxidase found in the cytosol in resting
cells. Upon cell activation, it translocates to the phagosome membrane and
associates with gp22phox, gp47phox, and gp91phox to form the active complex
capable of the generation of ROS during the respiratory burst.
[287, 288]
[289]
Function
Refs.
[4, 290]
[291]
[292294]
[295]
Function
Refs.
[296, 297]
[299]
[155]
[155, 300]
[301]
[155]
[155, 302]
[155, 298]
[303]
[305, 306]
[304]
173
thereby increasing CD4 differentiation. IFN- also influences nave CD4 cell differentiation toward a Th1 phenotype
more directly. The phenotype adopted by a naive T cell during
T cell activation is heavily influenced by the cytokine milieu
present at the time of T cell receptor engagement. IFN- and
IL-12 are the prototypic cytokines directing Th1 differentiation
during the primary response to antigen, and IL-4 directs differentiation of Th2 populations. IFN- induces IL-12 production in phagocytes [296] and inhibits IL-4 secretion by Th2
populations [39], which may further drive Th1 differentiation
in vivo.
IL-12 and IFN- coordinate the link between pathogen
recognition by innate immune cells and the induction of specific immunity, by mediating a positive feedback loop to amplify the Th1 response [4]. LPS and other pathogen-associated
molecular patterns directly trigger IL-12 production upon recognition by macrophages, DCs, and neutrophils [316 319],
which in turn induces IFN- secretion in antigen-stimulated,
naive CD4 T cells and NK cells [320, 321]. IL-12-induced
IFN- participates in positive feedback by further promoting
IL-12 production in macrophages [296, 297]. This amplification may be important in initiation or stabilization of the Th1
response (reviewed in refs. [4, 322]). IL-18 is highly synergistic
with IL-12 for IFN- production and has important functions in
the in vivo Th response [23, 24].
Secretion of large amounts of IFN- or IL-4 is the defining
feature of Th1 or Th2 cells, respectively [323]. These cytokines
function to directly promote cell-mediated immunity (IFN-) or
humoral immunity (IL-4) and to reciprocally antagonize each
others actions, further polarizing the response (reviewed in ref.
[108]). For example, IL-4 inhibits IFN--dependent activation
of macrophage-effector functions [324, 325]. Conversely,
IFN- antagonizes IL-4-dependent induction of the IgE receptor, FcRII [326].
c-myc expression through multiple pathways, including suppression of Rb phosphorylation, resulting in decreased E2F
activity as well as Rb-independent pathways, which may be a
result of PKR action [251]. In its active form, c-myc is associated with max, and the myc:max heterodimer activates transcription of genes required for cell cycle progression [265]. The
level of active myc is negatively regulated by mad1, which
sequesters the max coactivator away from myc and suppresses
transcription of myc-inducible genes [259]. In this way, the
mad1-to-c-myc ratio determines whether a cell will proliferate
(as a result of high levels of myc:max) or arrest in G1 (as a
result of high levels of mad1:max) [259, 260]. In addition to
decreasing the abundance of myc, IFN- increases mad1 levels, thereby further antagonizing myc activity and inhibiting
CSF-1-dependent proliferation in BMM [347].
Apoptosis is a process in which the cell directs its own
demise by activating intrinsic suicide machinery (reviewed in
refs. [337, 348]). In macrophages, apoptosis may be desirable
to prevent colonization by intracellular pathogens. Conversely,
many pathogens actually induce host-cell death through secretion of macrophage-specific toxins. Induction of apoptosis by
signals such as DNA damage requires the IRF-1 tumor-suppressor gene [165, 266, 267]. Levels of IRF-1 may be a
deciding factor in whether IFN- induces or protects from
apoptosis on treated cells [35, 349, 350]. It is proposed that
IFN- treatment of cells with high levels of functional IFNGR
very rapidly activates Stat1, thereby producing high levels of
IRF-1 that are able to induce apoptosis. In contrast, IFN-
treatment of cells with low levels of functional IFNGR may
activate Stat1 more slowly, thereby producing lower levels of
IRF-1 that are not sufficient to induce apoptosis [35]. Experiments in which overexpression of functional IFNGR on normally low-level IFNGR-expressing cells changed the IFN-
response of these cells from an antiapoptotic/proliferative phenotype to a proapoptotic phenotype are consistent with this
hypothesis [35]. This may also explain why myeloid cells are
more sensitive to the proapoptotic actions of IFN- than other
cells such as T cells, as myeloid cells express relatively high
numbers of functional IFNGR on the cell surface [35].
Many of the proapoptotic effects of IRF-1 are mediated by
the IRF-1-induced caspase 1 (IL-1-converting enzyme) [267
269]. Caspase 1 is a cysteine protease implicated in mediating
macrophage apoptosis by various stimuli including LPS [351
353] and is involved in generation of bioactive IL-1 and IL-18
[354]. Caspase 1 expression and resulting apoptosis can be
IFN--inducible [269] or can occur through IFN--independent IRF-1 activity [267]. IFN- also induces a number of
other proapoptotic molecules. These include PKR, the DAPs,
cathepsin D, and surface expression of Fas and the TNF-
receptor (Table 1).
tion, tryptophan depletion, and up-regulation of lysosomal enzymes promoting microbe destruction (Table 1) [222]. Similar
microbicidal mechanisms are activated by IFN- in neutrophils [4].
Macrophages kill bacteria, viruses, protozoa, helminths,
fungi, and tumor cells primarily by production of ROS and
reactive nitrogen intermediates (RNI) via induction of the
NADPH oxidase system and iNOS, respectively (reviewed in
refs. [281, 355, 356]). ROS and RNI use the advantages of low
molecular weight, reactivity, and lipophilicity to easily penetrate the microbial cell wall/coat to inflict injury. The importance of these molecules in host defense is highlighted by the
highly pathogen-susceptible phenotype of mice doubly deficient in NADPH oxidase and iNOS enzymes [357]. The timeframes and situations in which macrophage use these cytocidal
activities are generally different. ROS production becomes
apparent within 1 h after stimulus, whereas RNI generation
requires 24 h after encountering a pathogen product. In
general, ROS are used to target extracellular pathogens during
phagocytosis or that are too large for phagocytosis, whereas
RNI target intracellular pathogens and upon appropriate stimulus, extracellular pathogens and tumor cells.
NO is produced in the NADPH-dependent conversion of
L-arginine to L-citrulline by the NOS enzymes (NOS13). The
NOS2/iNOS isoform alone is inducible by cytokine and/or
microbial stimulus [281]. The NO generated by this enzyme
exists in equilibrium among a number of different redox states
(called RNI in this review) that have differing biological activities. It should be noted that much of the work presented
below applies to mice rather than humans, and there is at
present much controversy of the physiological relevance of NO
production in human host defense (reviewed in ref. [281]).
A wealth of evidence supports a crucial function of iNOS
and RNI in host defense (reviewed in ref. [281]). IFN-dependent RNI production is associated with increased ability
of phagocytic cells to kill ingested pathogens, and this ability
is inhibited by the addition of a substrate analog inhibitor of
iNOS such as N-methyl-L-arginine [358 361]. Furthermore,
mice in which the iNOS gene has been mutated show greater
susceptibility to parasitic infection and a dampened, nonspecific inflammatory response [362]. Production of RNI also
inhibits replication of a range of viruses, through ill-defined
mechanisms [358, 363, 364].
IFN- induces RNI production by up-regulating expression
of substrate, cofactor, and catalyst required for NO generation.
IFN- up-regulates argininosuccinate synthetase (which produces the L-arginine substrate), GTP-cyclohydroxylase I
(which supplies the tetrahydrobiopterin cofactor required for
NO production), and the iNOS enzyme [285, 286, 365367].
Maximal induction of iNOS transcription requires priming
and triggering stimuli such as priming with IFN- and
subsequent triggering with LPS or TNF- [368, 369]. The type
I IFNs cannot fully substitute for IFN- in triggering NO
production [368].
Superoxide and its reactive products are also important toxic
effector molecules of the nonspecific cytotoxic response. The
superoxide anion, O2, is generated by the multicomponent
flavocytochrome enzyme phagocyte oxidase during a process
called respiratory burst. This enzyme is composed of two
cytochrome b558 subunits, gp91phox and gp22phox, concentrated in the phagosome membrane, and two cytosolic components, p47phox and p67phox. Upon appropriate stimulus (e.g.,
phagocytosis), the cytosolic components translocate to the
membrane to form the active complex, which generates superoxide in the phagosome through transfer of a transported electron to molecular oxygen. The superoxide anion generated by
the respiratory burst spontaneously reacts to form hydrogen
peroxide (H2O2), hydroxyl radicals (OH), and hypochlorous
acid (HOCl) [281]. The toxic oxidants produced by the respiratory burst are also able to react with those produced by iNOS,
thereby forming a large number of different toxic species (e.g.,
peroxynitrite) to mediate cytotoxicity by a wide variety of
mechanisms [281, 370, 371].
The primary mechanism of IFN--induced up-regulation of
ROS production in phagocytes is transcriptional induction of
the gp91phox and p67phox subunits of the NADPH oxidase
complex [287289, 372]. The biological importance of this
pathway in host defense is emphasized by the human genetic
disease, chronic granulomatous disease, caused by defects in
the NADPH oxidase system and characterized by recurrent and
often fatal infections.
IFN- also promotes microbe destruction by augmenting
surface expression of the high-affinity FcRI on mononuclear
phagocytes, thereby promoting antibody-dependent, cell-mediated cytotoxicity [291]. Complement-mediated phagocytosis is
also up-regulated by IFN- through increased complement
secretion and complement receptor surface expression on
mononuclear phagocytes [292].
Tryptophan depletion from cells in response to IFN- may
be an antiparasitic mechanism in humans [373]. IFN- upregulates the expression of indoeamine 2,3 dioxygenase, an
enzyme responsible for the generation of N-formylkynurenine
from tryptophan [374 377]. It is interesting that IFN- also
induces expression of tryptophanyl-tRNA synthetase, a housekeeping gene that catalyzes tRNA Trp aminoacetylation during
protein synthesis [378, 379]. It is proposed that this enzyme
may also aid in tryptophan depletion by incorporating free
tryptophan into translating protein and may ensure synthesis of
Trp-rich proteins with immunologically important functions
(e.g., the IRF family and many MHC molecules) during cellular
tryptophan depletion [380].
LBP
MD-2
LPS
CD14
TLR4
1
Cytosol
MyD88
MyD88-dependent
pathway
IRAK
TRAF6
IRF-3
NIK
MyD88-independent
pathway
TRIF?
p38 MAPK
JNK/SAPK
ERK
IKK
Rapid activation of
NFB and AP-1
Slow activation of
NFB and AP-1
4
NF-B
5
AP-1
Transcription of IFN/
Nucleus
Fig. 3. The current paradigm for optimal LPS signal transduction through TLR4. The LPS:LPS-binding protein (LBP) complex binds to CD14. The LPS:LBP:CD14
complex probably activates TLR4, and optimal LPS-induced signaling requires the association of the MD-2 accessory component with the TLR4 extracellular
domain. Downstream signaling is dependent on sequential recruitment and activation of signaling molecules. In the MyD88-dependent pathway, the signaling
adaptor MyD88 is recruited to the receptor, and the signal is relayed via sequential recruitment and activation of the serine/threonine kinase IL-1R-associated
kinase (IRAK), TNF receptor-associated factor (TRAF)6, NF-B-inducing kinase (NIK), and IB kinase for the rapid activation of NF-B and AP-1 (IKK). MyD88
adaptor-like/Toll/IL-1 receptor/resistance (TIR) domain-containing adaptor protein also contributes to the MyD88-dependent pathway, through ill-defined
mechanisms. The MyD88-independent pathway is less well characterized but involves activation of IRF-3 and more slowly activates NF-B and AP-1. It has
recently been suggested that TIR domain-containing adaptor-inducing IFN- (TRIF) participates in the MyD88-independent pathway upstream of IRF-3.
Activation of the MyD88-dependent and -independent pathways also activates the mitogen-activated protein kinase (MAPK) pathways, c-Jun N-terminal kinase
(JNK)/stress-activated protein kinase (SAPK), p38 MAPK, and extracellular-regulated kinase (ERK) pathways. The MyD88-dependent pathway ultimately controls
transcription of target genes, including many of the proinflammatory cytokines implicated in the pathophysiology of septic shock. Genes regulated by the
MyD88-independent pathway, however, do not contribute to septic shock to the same extent. Possible mechanisms giving rise to the priming effect apparent when
LPS-stimulated macrophages are pretreated with IFN- include (numbered on the figure): (1) IFN- up-regulates expression of the TLR4 and MD-2 components
of the LPS recognition complex; (2) IFN- upregulates expression of MyD88 and IRAK; (3) LPS activates Stat1, possibly through the MAPK pathway, thus
augmenting the IFN- response; (4) IFN- promotes LPS-induced NF-B activation; (5) LPS induces type I IFN, which may participate in cross-talk with the IFN-
signaling pathway to augment the macrophage IFN- response; and (6) LPS/TNF-- and IFN--activated/induced signaling molecules can often bind to promoter
regions of target genes to synergistically regulate transcription. GARG, Glucocorticoid attenuated response gene; IRG, immune-responsive gene.
IFN- priming in vivo, as it demonstrates that IFN- is normally produced during the response to LPS and acts to amplify
LPS-induced cellular responses. The priming phenomenon relies on IFN- and LPS reciprocal cross-regulation of signaling
molecules of the other pathway.
IFN- influences LPS-dependent signaling capabilities by
promoting ligand-receptor interactions as well as downstream
signaling machinery. Efficient LPS:TLR4 interaction requires
the MD-2 and CD14 accessory molecules, and subsequent
maximal signaling requires MyD88 signaling adaptor. In a
number of experiments, IFN- was shown to promote transcription of TLR4, subsequent TLR4 surface expression, and LPSbinding ability in macrophages [395397]. Furthermore, IFN-
of the p50 subunit of NF-B but only low levels of p65. IFN-
priming caused an increase in p65 mRNA as a result of
increased transcript stability.
Many IFN--inducible genes are also TNF--inducible, and
these genes are often superinduced by the combination of these
factors [366, 372, 401, 402]. TNF- is a macrophage-derived
cytokine secreted in response to LPS, which can act in an
autocrine manner to mediate many LPS-induced effects via
NF-B [403]. IFN- priming of TNF- responses is thus
responsible for the priming of a subset of LPS-induced genes.
In many cases, synergistic induction by the combination of
these factors may be a result of the combined presence of Stat1
and NF-B-binding sites in the promoter elements of responsive genes [160, 404]. Synergy may be also be a result of
cross-talk between the IFN- and TNF- signaling pathways:
TNF- stimulation is able to induce transcription of IRF-1 and
promotes IFN--induced Stat1 activation [405, 406]; IFN-induced PKR is able to signal to NF-B [407]; and IFN-
increases surface expression of the TNF- receptor [280, 408,
409], although the significance of this is uncertain, as an
increased receptor expression level has not been linked with
increased response to TNF- [410, 411].
Although probably not complete, these mechanisms of increasing cellular sensitivity to LPS may start to explain the
shift in the LPS dose-response curve seen with IFN- priming.
Genes that need IFN- and LPS treatment for induction may
require a certain threshold of LPS signaling for transactivation,
and so IFN- treatment shifts the LPS dose-response curve by
increasing cellular sensitivity. Alternatively, these genes may
require specific cross-talk between pathways before transcriptional activation can occur. Examples of such cross-talk may
include LPS-induced Stat1 serine phosphorylation or crosstalk between IFN-- and LPS-induced type I IFN pathways.
LPS is able to promote the IFN- signaling pathway through
Stat1. As noted earlier, phosphorylation of S727 of Stat1 occurs
in response to IFN- or LPS exposure and is necessary for
maximal Stat1 activation. LPS treatment following IFN- exposure increases the percentage of molecules phosphorylated
on Y701 and S727 and subsequent Stat1 DNA-binding activity
relative to IFN- treatment alone, thereby augmenting IFN-dependent, Stat1-mediated gene expression [123, 223]. IFN-
and LPS may use different pathways for Stat1 serine phosphorylation, as LPS-induced Stat1 serine phosphorylation is sensitive to a p38 MAPK inhibitor, whereas the serine phosphorylation induced by IFN- is not [110]. Another study suggested
that although p38 MAPK is necessary, it is not sufficient for
Stat1 serine phosphorylation by LPS, and protein kinase C- is
also required to mediate phosphorylation [412]. In addition to
promoting serine phosphorylation, LPS treatment following
IFN- exposure augments Stat1 tyrosine phosphorylation of
residue 701 [399]. Macrophage exposure to LPS triggers production of endogenous type I IFN that can act on the macrophage population in an autocrine/paracrine manner. This has
been identified as the causal agent of LPS-induced Stat1
tyrosine phosphorylation [413].
It has long been recognized that LPS induces transcription of
type I IFN [414], but only in recent years has the significance
of autocrine/paracrine functions of type I IFN in mediating
LPS-induced gene expression been acknowledged [391, 415,
178
CONCLUDING REMARKS
IFN- is a remarkable cytokine that orchestrates many distinct
cellular programs through transcriptional control over large
numbers of genes. Many IFN--induced effects resulting in
heightened immune surveillance and immune system function
during infection have been discussed in this review. As pathogen products such as LPS and CpG DNA augment local IFN-
production, and IFN- augments the immune system response
to these agonists, an important function of IFN- during in vivo
infection is suggested, whereby IFN- participates in an amplification loop to increase immune system sensitivity and
response to pathogens. This model is supported by the in vivo
and in vitro priming phenotype apparent when LPS-stimulated
macrophages are pretreated with IFN-, and also by the high
resistance of IFNGR/ mice to LPS-induced septic shock.
The ability of IFN- to synergize or antagonize the effects of
cytokines, growth factors, and pathogen-associated molecular
pattern (PAMP)-signaling pathways (e.g., TNF-, IL-4, CSF-1,
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