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PRO- versus ANTI-INFLAMMATORY CYTOKINES:
MYTH OR REALITY
Department of Physiopathology, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France
Fax: +33 (0)1 40 61 31 60; E-mail: firstname.lastname@example.org
Received November 8, 2000; Accepted November 17, 2000
Abstract - Inflammation is characterized by an interplay between pro- and anti-inflammatory cytokines. Cytokines are commonly
classified in one or the other category: interleukin-1 (IL-1), tumor necrosis factor (TNF), gamma-interferon (IFN-
γ), IL-12, IL-18
and granulocyte-macrophage colony stimulating factor are well characterized as pro-inflammatory cytokines whereas IL-4, IL-10,
α and transforming growth factor-β are recognized as anti-inflammatory cytokines. In this review, we point out that
this classification is far too simplistic and we provide numerous examples illustrating that a given cytokine may behave as a pro-
as well as an anti-inflammatory cytokine. Indeed, the cytokine amount, the nature of the target cell, the nature of the activating
signal, the nature of produced cytokines, the timing, the sequence of cytokine action and even the experimental model are
parameters which greatly influence cytokine properties.
Key words: Inflammation, interleukin, chemokine, macrophages, neutrophils, endothelial cells
Cytokines play an important role during the
inflammatory process. Two cytokines, namely
interleukin-1 (IL-1) and tumor necrosis factor (TNF)
orchestrate the inflammatory response and initiate a
cascade of mediators which are directly responsible for the
various events associated with inflammation (e.g.
increased vascular permeability, chemoattraction of
circulating leukocytes, proteolysis…). Other cytokines
such as IL-3 and granulocyte-macrophage colony
stimulating factor (GM-CSF) amplify the release of IL-1
and TNF, thus favoring the inflammatory process. This is
also the case for gamma-interferon (IFN-
γ) the production
of which is induced by IL-12 and IL-18. While the
cytokines mentioned above are classified as "pro-
inflammatory cytokines", IL-4, IL-10, IL-13, interferon-
α) and transforming growth factor-β(TGF-β)
are recognized as anti-inflammatory cytokines because of
their ability to inhibit the release of pro-inflammatory
cytokines, to induce the production of IL-1 receptor
antagonist (IL-1ra) and the release of soluble TNF
receptor (sTNFR) and to limit some of the pro-
inflammatory activities of IL-1 and TNF. However, the
events occurring during inflammation are not as simplistic
as an interplay between pro- and anti-inflammatory actors.
Indeed, they are far more complex ! In this short review
we will provide some examples which illustrate the fact
that each of these cytokines offers a "half angel - half
devil" aspect and none can be simply labelled either "pro"
A TOO SIMPLISTIC DICHOTOMY
René Magritte, the surrealistic Belgium artist, painted
a pipe on a picture and wrote "Ceci n’est pas une pipe"
This is not a pipe). It is becoming more and more frequent
to find reports reminiscent of this concept: e.g. "TNF is not
a pro-inflammatory cytokine". For example, in their report
entitled "TNF is a potent anti-inflammatory cytokine in
autoimmune-mediated demyelination" Liu
et al. (42)
showed that in response to injection of myelin
oligodendrocyte glycoprotein, TNF-deficient mice of
different genetic backgrounds displayed a multiple
sclerosis-like disease with a higher incidence, a higher
mortality, a longer duration and a more severe auto-
immune disease than their wild type counterparts.
Similarly, in an experimental model of collagen-induced
arthritis, it was found that blocking the activity of IFN-
(either by anti-IFN-γantiserum or by using IFN-γreceptor
Cellular and Molecular Biology
47 (4), 000-000 0145-5680/01
Printed in France. 2001 Cell. mol. Biol.
knock-out mice) resulted in an accelerated onset of the
disease (70). These results suggested that IFN-
γ, instead of
being a pro-inflammatory cytokine, was rather involved in
counteracting the development of the disease in this
experimental model. As well, one can assert that "IL-10 is
not an anti-inflammatory cytokine". Evidence comes from
in vivo works in which pro-inflammatory or
immunostimulating activities have been reported for IL-10.
This is the case for autoimmune diabetes whose onset and
development are accelerated in transgenic mice
overexpressing IL-10 in pancreatic islets (52,74). Also, IL-10
treatment accelerates allograft rejection of islet cells (77)
and heart (56). In a model of endotoxin-induced uveitis,
intra-peritoneal injection of IL-10 potentiated the ocular
inflammation (59). Finally, in a tumor model, IL-10 was
reported to favor tumor rejection (6) and using transfected
mouse mammary adenocarcinoma cells expressing IL-10,
et al. (20) showed that the tumor growth area was
associated with an enhanced level of the chemokine
"monocyte-chemoattractant protein-1" (MCP-1) and of
inducible nitric oxide synthase (iNOS), an enhanced
expression of VCAM-1 and ELAM-1 adhesion molecules
and an enhanced recruitment of leukocytes as compared to
mice receiving the parent adenocarcinoma. This parallels
the fact that IL-10 induces E-selectin expression on small
and large blood-vessel endothelial cells (71).
We will now review few parameters which influence
the behavior of the different cytokines and may explain
why, depending upon the situation, both pro- and anti-
inflammatory properties can be described for the same
THE AMOUNT OF CYTOKINE
The intensity of the inflammatory response is
associated with different physiological events which
correlate with the levels of the produced cytokine. The
pro-inflammatory cytokines are the most necessary
mediators to set-up an anti-infectious response; however,
an exacerbated production of these cytokines may be
deleterious and even lead to death when used in animal
models and be associated with poor outcome in human
pathologies such as sepsis. On the other hand, while anti-
inflammatory cytokines are a prerequisite to control the
cascade of pro-inflammatory mediators, their excessive
production is associated with a severe immune depression
as observed in patients following trauma or major surgery.
Consequently, an increased sensitivity to nosocomial
infections is observed in these patients.
The amount of a given cytokine clearly influences its
properties. The best example is given with TGF-
β (9): in
addition to its role in controlling inflammation, TGF-
restrains cell proliferation and controls turnover of the
extracellular matrix. At high concentration, TGF-
suppresses cell proliferation and stimulates the production
of pathological amounts of extracellular matrix (fibrosis)
whereas at low levels, TGF-
β predisposes to excessive
cell proliferation, atherogenesis or reduced production of
extracellular matrix and impaired wound healing.
Similarly, it has been reported that some effects of TNF
were influenced by the amount of this cytokine used in the
experimental model. Low doses were found to induced
angiogenesis whereas high concentrations were associated
with an inhibition of angiogenesis (23). Moreover, in an
elegant experimental model of arthritis induced by the
injection of acidified type II collagen, it was demonstrated
that low amounts of IL-12 were pro-inflammatory
whereas 100 fold higher amounts were associated with an
anti-inflammatory process (37). Injection of 5 ng of IL-12
a day increased the severity of the disease, a property
which was essentially TNF-dependent whereas treatment
with 500 ng a day significantly decreased the mean
arthritis index of the pathology, a phenomenon which was
essentially IL-10-dependent. Interestingly, only large
amounts of IL-12 induced circulating corticosterone.
THE NATURE OF THE TARGET CELL
The anti-inflammatory properties of our quintet of
anti-inflammatory cytokines have essentially been coined
with monocytes/macrophages used as target cells. There
are numerous examples which illustrate that the story
might be completely different with other target cells. Thus,
IL-10 was first identified and defined as a cytokine
capable to repress the production of IFN-
γ by Th1 clones
(25), but more recently it was demonstrated that IL-10
enhanced the production of IFN-
γ by NK cells (63),
increased the intracellular expression of IFN-
γand IL-2 in
T-cells in combination with IL-2 after antigen
stimulation (60) and increased the number of IL-2
T-cell clones (40). Furthermore, IL-4 and
IL-10 which inhibit the LPS-induced production of IL-8
by macrophages, amplify that of endothelial cells (18).
The different efficiency to inhibit IL-8 production
depending on the nature of the target cells has also been
reported for INF-
α which limits this production by LPS-
activated peripheral blood mononuclear cells and by TNF-
stimulated bone marrow stroma cells but which is
inefficient when acting on LPS-activated neutrophils (2).
While IL-13 diminishes chemokine production by
2 J.-M. Cavaillon
activated macrophages, it induces the synthesis of MCP-1
by endothelial cells (29). While TGF-
β1 limits the
production of IL-1α and IL-8 in macrophages, it induces
them in epithelial cells (38). While IL-10 can repress the
production of nitric oxide (NO) by macrophages or
keratinocytes (4,13), it does not modify NO release by
mesangial cells (26) and even enhances the production of
NO by bone marrow derived macrophages and osteoclasts
(7,65). Acting on bone marrow derived mast cells, IL-10
synergized with c-kit ligand and LPS to increase the
production of cyclooxygenase type 2 and PGD2 as well as
the expression of IL-6 mRNA (51). When addressing the
regulation of IL-1
β-induced IL-6 production by
et al. (55) showed that IL-10 but
neither IL-4 nor dexamethasone possessed inhibitory
The target cell status may modify its reactivity as well.
Accordingly, IL-10 alone or in synergy with TNF
enhances HIV replication and TNF production by HIV-
infected T-cells or promonocytic cells (24,57). Most
importantly, environmental parameters may also influence
the reactivity of a given cell type. The best example is
provided by the study of Pang
et al. (53) who reported in
chronic bronchial sepsis that IL-10 was able to inhibit the
LPS-induced IL-8 production by circulating neutrophils
but was unable to do so when the same assay was
performed with sputum-derived neutrophils. Similarly,
analysis of spontaneous NO generation by macrophages
from inflamed, but not normal glomeruli, was down-
regulated by the addition of IL-4 or TGF-
Discrepancies have also been reported in terms of the
induction of adhesion molecules. For example, IL-4
inhibits the IL-1- or TNF-induced expression of ICAM-1
and ELAM-1 on the surface of endothelial cells, but it
induces ICAM-1 expression in human epithelial cells (64)
and favors the expression of VCAM-1 on endothelial
cells, allowing the adherence of basophils and eosinophils
(62). On the other hand, IL-10 inhibits ICAM-1
expression on human Langerhans cells but not on
keratinocytes, dermal endothelial cells or fibroblasts (12).
THE NATURE OF THE
The inhibitory capacity of the so-called anti-
inflammatory cytokines may also depend on the nature of
the triggering agent which acts simultaneously on the
target cell. For example, we have shown that IL-4 and IL-10
repress the LPS-induced IL-8 production by neutrophils
while this is not the case when neutrophils were activated
α (47). Surprisingly, the production of IL-1ra by
activated neutrophils did not reflect what was described
for the inhibition of IL-8: we reported that IL-10 was not
acting in synergy with LPS but was active when used
simultaneously with TNF-
α to further enhance the
production of IL-1ra (46). In contrast, IL-4 amplifies the
production of IL-1ra by neutrophils, independently of the
nature of the activating signals. The studies on the
modulation of the production of various chemokines led to
a rather complex pattern. Thus, it has been reported that
IL-4 did not affect the production of RANTES by IFN-
activated human monocytes whereas it was capable to
increase this production when the cells were activated
α (44). In the presence of IL-2, the production
γ by splenocytes from scid mice was unchanged
when the cells were cultured with IL-12 and TNF-
whereas this production was greatly inhibited when the
cells were activated with heat-killed
(67). When the proliferation of CD8
T-cells was monitored in the presence of IL-10, the
proliferative response could be either reduced (in the
presence of allogenic monocytes), or unchanged (in the
presence of anti-CD3 antibodies) or even enhanced (in the
presence of IL-2) (30). Studies on the induction of tissue
factor on the surface of monocytes or endothelial cells also
revealed major differences based on the nature of the
activating signal: IL-4 and IL-13 fully inhibited the
induction of the expression of tissue factor on the surface
of endothelial cells activated with LPS, whereas there was
no inhibition when IL-1
βwas used as the triggering agent
(32). A totally different pattern was obtained when tissue
factor expression was analyzed on the surface of
THE NATURE OF THE
The capacity of a given cytokine to inhibit the
production of others may also vary depending on the
nature of these other cytokines. For example, TNF was
surprisingly shown to be a potent inhibitor of IL-12
secretion from human monocyte-derived macrophages
activated with either LPS or
whereas no similar inhibitory activity was reported when
addressing the production of IL-1
α, IL-1β and IL-6 (45).
Similarly, the so-called anti-inflammatory cytokines do
not inhibit the production of all cytokines. Thus, IL-10
reduces the production of IL-12 by CD40L-activated
dendritic cells whereas it does not modify the production
of IL-8 and TNF-
α (11). We reported that in whole blood
Pro- versus anti-inflammatory cytokines 3
samples activated by heat-killed Streptococcus pyogenes,
IL-13 inhibited the production of IL-8 but was unable to
modify that of TNF-
α (45). In addition, when the effects
of IL-4 were studied on monocytes cultured for 7 days, it
was demonstrated that the LPS-induced IL-1
was reduced whereas the TNF-
α production was
unaffected (31). Studying IL-1
α-activated human bone
marrow stroma cells, IL-4 was also shown to enhance the
IL-8 production but to inhibit that of leukemia inhibitory
factor (LIF) (19). The field of chemokines offers
numerous examples of different regulations induced by
the same cytokine. For example, IL-4 acting on
macrophages inhibits the production of IL-8 and MIP-1
but favors the release of MCP-1, RANTES, AMAC-1 and
C10. A completely different profile might be found when
considering another target cell. Thus, IL-4, when acting on
endothelial cells favors the production of IL-8 and MCP-1
but limits that of RANTES. A similar heterogeneity in
terms of responsiveness has also been reported with IFN-
which enhances the production of IP-10 and RANTES by
macrophages but inhibits the production of GRO, MIP-1
β and AMAC-1.
The fact that a mediator exerts an inhibiting or, on the
contrary, an enhancing effect may also be linked to the
timing of its exposure to the target cells. For example,
IL-4 and IL-13 inhibit IL-6, IL-12, MCP-1 and TNF
production when added simultaneously to activated
monocytes whereas they enhance the production of these
cytokines when they are delivered before the activating
signals (16,36,50). When IL-4 was added simultaneously
α, it had a very low capacity to reduce the
induction of tissue factor expression on the surface of
endothelial cells (32). Conversely, a pre-treatment of the
cells with IL-4 for 8 to 16 hr allowed a significant
inhibition (48). In an elegant model of resistance to
Pseudomonas aeruginosa infection, Giampietri
et al. (28) demonstrated that a 24 hr pre-treatment of mice
with IL-4 was protective when high number of CFU were
injected whereas when injected only 1 hr before the
bacterial challenge with a lower number of CFU, IL-4 was
deleterious. In the first case enhanced survival was
associated with a reduced level of circulating TNF while
in the later one reduced survival was associated with an
enhanced level of circulating TNF. Another fascinating
example of timing is provided by the effect of cortisol
infusion in human volunteers. While an injection of LPS
at the end of the cortisol infusion did not lead to detectable
circulating TNF, the same injection made 12 to 144 hr
after the infusion led to far higher levels of TNF and IL-6
than those reached in the same volunteers who did not
receive the cortisol pre-treatment (3).
THE SEQUENCE OF CYTOKINE ACTION
Cytokines are the words of a universal language used
by cells. As in any language, the order of the words
influences the meaning of the sentence. Accordingly, the
sequence of exposure to cytokines plays a key role in the
nature of the signals delivered to the cells. For example,
TNF and INF-
γ used simulataneously have no significant
effect on the production of NO by rat bone marrow-
derived macrophages. In contrast, IFN-
γ primes the cells
which then produce significant amounts of NO when
exposed to TNF. Most interestingly, if the cells are first
exposed to TNF, then 4 hrs later to IFN-
γ and after an
additional 4 hrs finally exposed to TNF, they do not
produce any NO (21). The same desensitization was
observed with a pre-treatment with IL-4 or TGF-
whereas IL-10 had no inhibitory activity in this model. A
similar observation has been made when the LPS-induced
production of IL-12p70 was investigated (33): cells pre-
exposed to IFN-
γ, produced significant amounts of IL-12
whereas low or no production was obtained with cells pre-
treated with either TNF or TNF + IFN-
THE EXPERIMENTAL MODEL
We have studied in vitro the effect of IL-10 pre-
treatment on the production of TNF and IL-6 by
leukocytes upon stimulation by LPS. We reported that in
the presence of IL-10, the prevention of monocyte
adherence by red cells in the whole-blood assays or by
cultures of peripheral blood mononuclear cells on
Teflon®, allowed a higher cytokine production as
compared to cells maintained in culture medium alone
before the LPS activation. When the first step of the
experiment was performed on plastic (i.e. with adherence
of monocytes) the classical inhibitory activity of IL-10
was found (1). Altogether, these results indicate that IL-10-
induced modulation of cytokine production depends on
in vitro experimental procedures. More recently, a
similar "pro-inflammatory" activity of IL-10 was
reported in human volunteers receiving an LPS injection
(39). The use of different
in vivo models may result in
completely opposite conclusions. Indeed, in a model of
immune complex-induced acute lung injury it was
reported that the neutralization of IL-13 increased the
4 J.-M. Cavaillon
inflammatory process, suggesting that endogenous IL-13
restrained inflammation (41). In contrast, transgenic mice
over-expressing IL-13 in the lungs showed an
inflammatory mononuclear infiltrate, eosinophils around
airways and in parenchyma, an airway epithelial
hypertrophy, a goblet cell hyperplasia, a hyperproduction
of mucus and a selective local production of the eotaxin
chemokine (78). This last paper is reminiscent of the
inflammatory role of IL-13 demonstrated in various
models of asthma (73).
We already mentioned the protective role of IFN-
model of collagen-induced arthritis and the accelarated
onset of the disease in IFN-
γ-KO mice (70). Billiau’s
group further demonstrated that this observation was only
true when collagen was injected together with complete
Freund adjuvant (CFA). Indeed, when incomplete Freund
adjuvant was employed, the disease did not occur in the
γ receptor knock-out animals (49). The authors
demonstrated that on one hand IFN-
γ induced pro-
inflammatory cytokines such as TNF and IL-12, on the
other hand, in the model using CFA (i.e. associating
Mycobacteria), IFN-γ had a beneficial role by restraining
both the expansion of hematopoietic process and the
number of macrophages, a major source of pro-
IL-6, THE PARADIGM OF AMBIGUITY!
Acute phase proteins are essentially protective and
limit the inflammatory process. They possess anti-
protease and some scavenger activities. Accordingly, IL-6
can be considered as an anti-inflammatory cytokines
thanks to its potency to induce the release of acute phase
proteins by hepatocytes, including IL-1ra (27). It was also
mentioned that IL-6 inhibited the release of IL-1 and TNF
(61) and favored that of soluble TNF receptor (66).
Accordingly, numerous experimental models, including
systemic or local endotoxemia demonstrated the
protective activity of IL-6 (75,76). However, in contrast,
IL-6 can induce bone resorption (34), muscle atrophy
(68), anemia (35) and can prime neutrophils for the
production of PAF and superoxide anion (8,10). While IL-6
does not activate endothelial cells, it induces MCP-1, -3
and IL-8 production, STAT-3 activation, and ICAM-1
expression, in the presence of its soluble receptor which is
naturally found in plasma (58). Deleterious activities of
in vivo have been suggested by experimental models
of ischemia reperfusion and of lung injury performed in
IL-6 knock-out mice which were shown to exhibit lower
inflamatory responses (14,15).
We have to admit that dogma often result from an over-
simplification of the described phenomena. Accordingly,
dogma are made to be broken! It appears that the
inflammatory response is an extremely complex interplay
of mediators whose exact contribution may depend on
many influencing parameters. Finally, to add to the
complexity, one should not forget that humans are not
equal in terms of their inflammatory responses. The
known genetic polymorphisms for many pro- as well as
anti-inflammatory cytokines (17,54,69,72) are associated
with the amplitude of the inflammatory process. In
addition, another polymorphism exists in terms of target
cell reactivity in response to cytokine signaling (5). This
individual heterogeneity has also to be considered when
addressing the inflammatory response.
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