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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-gamma), IL-12, IL-18 and granulocyte-macrophage colony stimulating factor are well characterized as pro-inflammatory cytokines whereas IL4, IL-10, IL-13, IFN-alpha and transforming growth factor-beta 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.
Department of Physiopathology, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France
Fax: +33 (0)1 40 61 31 60; E-mail:
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,
IL-13, IFN-
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-
alpha (IFN-
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"
or "anti".
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
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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,
Di Carlo
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 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 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
secreting CD4
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
astrocytes, Pousset
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-
β (22).
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 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
by TNF-
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
with TNF-
α (44). In the presence of IL-2, the production
of IFN-
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 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
Staphylococcus aureus
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
β production
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
to TNF-
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).
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-
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-
γin a
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-
inflammatory cytokines.
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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... TNF-α and IL-6, when combined, increase the level of nuclear factor kappa beta (NF-κB), which induces some pro-inflammatory genes. Thus, inflammation continues to develop and progress (Cavaillon 2001;Liu et al. 2017;Metsios et al. 2020). Because TNF-α is not present during acute exercise, IL-6 does not exhibit pro-inflammatory properties. ...
... TNF-α and IL-1, the main regulators of the inflammatory response, are rendered ineffective as a result of these. As a result, cascades initiated by these two cytokines have been shut down, and the inflammation is under control (Cavaillon 2001;Metsios et al. 2020;Scheller et al. 2011). Various more cytokines are also released during acute exercise in addition to these. ...
... TNF-α and IL-6, when combined, increase the level of nuclear factor kappa beta (NF-κB), which induces some pro-inflammatory genes. Thus, inflammation continues to develop and progress (Cavaillon 2001;Liu et al. 2017;Metsios et al. 2020). Because TNF-α is not present during acute exercise, IL-6 does not exhibit pro-inflammatory properties. ...
... TNF-α and IL-1, the main regulators of the inflammatory response, are rendered ineffective as a result of these. As a result, cascades initiated by these two cytokines have been shut down, and the inflammation is under control (Cavaillon 2001;Metsios et al. 2020;Scheller et al. 2011). Various more cytokines are also released during acute exercise in addition to these. ...
... In our study, CUMS decreased the expression of IL-4 in PFC and increased it in HC. The experimental design conducted here does not provide an explanation for this alteration, but we can hypothesize that this is a consequence of the differential response to stress within brain structures, which might alter the pattern and the level of cytokine expression (Cavaillon 2001;Leff Gelman et al. 2019). ...
Full-text available
Physical and psychological stress modulates the hypothalamic pituitary adrenal (HPA) axis, and the redox and inflammatory systems. Impairments in these systems have been extensively reported in major depression (MD) patients. Therefore, our study aimed to investigate the effects of the intranasal administration of interleukin-4 (IL-4) in mice with depressive-like behavior induced by chronic unpredictable mild stress (CUMS) for 28 days. On the 28th day, mice received IL-4 intranasally (1 ng/mouse) or vehicle (sterile saline), and after 30 min, they were submitted to behavioral tests or euthanasia for blood collection and removal of the adrenal glands, axillary lymph nodes, spleen, thymus, prefrontal cortices (PFC), and hippocampi (HC). A single administration of IL-4 reversed CUMS-induced depression-like behavior in the tail suspension test and splash test, without evoking locomotor changes. IL-4 administration reduced the plasma levels of corticosterone and the increased weight of suprarenal glands in stressed mice. Moreover, IL-4 restored the expression of nuclear factor erythroid 2-related factor 2 (NRF2), nuclear factor kappa B (NF-kB), interleukin 1 beta (IL-1β), IL-4, brain derived neurotrophic factor (BDNF), and indoleamine 2,3-dioxygenase (IDO) in the PFC and HC and modulated oxidative stress markers in these brain structures in stressed mice. Our results showed for the first time the antidepressant-like effect of IL-4 through the modulation of neuroinflammation and oxidative stress. The potential effect of IL-4 administered intranasally arises as an innovative strategy for MD treatment.
... Overall, CSF-DCX/GPC2 were not associated with the clinical manifestations of infection of the patients, but an association was found with particular cytokines, namely IL-1β, IL-8, IL-2 and IL-13 for both DCX and GPC2. IL-1β, IL-8 and IL-2 are traditionally classified as proinflammatory cytokines, while IL-13 as anti-inflammatory, keeping in mind that some cytokines, depending on complex factors like environment or local concentration, display dual properties [39]. IL-1β is an important mediator of pro-inflammatory signaling, IL-8 is a chemokine involved in chemotaxis for neutrophils and in angiogenesis, IL-2 plays a role in T cell response, and IL-13 is considered as a T-cell helper type (T H )-2 cytokine [40]. ...
Full-text available
Objective: Doublecortin (DCX) and glypican-2 (GPC2) are neurodevelopmental proteins involved in the differentiation of neural stem/progenitor cells (NSPCs) to neurons, and are developmentally downregulated in neurons after birth. In this study, we investigated whether the concentrations of DCX and GPC2 in the cerebrospinal fluid (CSF) from human pediatric patients reflect this developmental process or are associated with cerebral damage or inflammatory markers. Methods: CSF was collected from pediatric patients requiring neurosurgical treatment. The concentrations of DCX, GPC2, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, and TNF-⍺) were measured using immunoassays. Results: From March 2013 until October 2018, 63 CSF samples were collected from 38 pediatric patients (20 females; 17 patients with repeated measurements); the median term born-adjusted age was 3.27 years [Q1: 0.31, Q3: 7.72]. The median concentration of DCX was 329 pg/ml [Q1: 192.5, Q3: 1179.6] and that of GPC2 was 26 pg/ml [Q1: 13.25, Q3: 149.25]. DCX and GPC2 concentrations independently significantly associated with age, and their concentration declined with advancing age, reaching undetectable levels at 0.3 years for DCX, and plateauing at 1.5 years for GPC2. Both DCX and GPC2 associated with hydrocephalus, NSE, IL-1β, IL-2, IL-8, IL-13. No relationship was found between sex, acute infection, S100B, IL-4, IL-6, IL-10, IFN-γ, TNF-α and DCX or GPC2, respectively. Conclusions: Concentrations of DCX and GPC2 in the CSF from pediatric patients are developmentally downregulated, with the highest concentrations measured at the earliest adjusted age, and reflect a neurodevelopmental stage rather than a particular disease state.
... Journal of Affective Disorders 249 (2019) 410-417 biomarkers in psychiatry (Treadway and Leonard, 2016). Furthermore, the distinction between pro-and anti-inflammatory cytokines represents a simplistic classification, since the same mediator of inflammation can determine an opposite effect depending on the nature of the target cell, the timing of exposure to that mediator and the nature of the triggering signal (Cavaillon, 2001), as we discussed for TNF-α. Cytokine levels were not able to predict the severity of depressive symptoms in patients with MDDin our sample. ...
... IL-6 * IL-11 * IFN-α * IFN-β * Abbreviations: IL; interleukin, IFN; interleukin, G-CSF; granulocyte colony stimulating factor, TNF; tumour necrosis factor, TGF; transforming growth factor. * Have contrasting mechanisms suggesting that the cytokine may be involved in both pro-and anti-inflammatory activities [69][70][71][72]. ...
Full-text available
The human gut is responsible for food digestion and absorption. Recently, growing evidence has shown its vital role in the proper functioning of other organs. Advances in microfluidic technologies have made a significant impact on the biomedical field. Specifically, organ-on-a-chip technology (OoC), which has become a popular substitute for animal models, is capable of imitating complex systems in vitro and has been used to study pathology and pharmacology. Over the past decade, reviews published focused more on the applications and prospects of gut-on-a-chip (GOC) technology, but the challenges and solutions to these limitations were often overlooked. In this review, we cover the physiology of the human gut and review the engineering approaches of GOC. Fundamentals of GOC models including materials and fabrication, cell types, stimuli and gut microbiota are thoroughly reviewed. We discuss the present GOC model applications, challenges, possible solutions and prospects for the GOC models and technology.
... However, as claimed 20 years ago, IL-6 is a paradigm of ambiguity (58), being protective as a key player of antiviral immunity, of antibody production, of airway ciliated cells regeneration, and of neutrophil survival, but can be pathogenic by favoring coagulation cachexia, and by stimulating a T H 17 response. Accordingly, the time window during the disease progression that would favor the targeting of IL-6 might be very much restricted (59,60). Thus, not surprisingly, some investigations led to conclude that the use of anti-IL-6 receptor antagonists (tocilizumab or sarilumab) improved outcomes, including survival (61)(62)(63), while others (64-66) did not demonstrate any benefit on disease progression, preventing intubation or death. ...
The COVID-19 pandemic has been a challenge to propose efficient therapies. Because severe SARS-CoV2 infection is a viral sepsis eventually followed by an immunological autoinflammatory phenomenon, many approaches have been inspired by the previous attempts made in bacterial sepsis, while specific antiviral strategies (use of interferon or specific drugs) have been additionally investigated. We summarize our current thinking on the use of SARS-CoV-2 antivirals, corticosteroids, anti–IL-1, anti-IL-6, anti-C5a, aswell as stem cell therapy in severe COVID-19. Patient stratification and appropriate time window will be important to be defined to guide successful treatment.
We present a Bayesian partial membership model that estimates the associations between an outcome, a small number of latent variables, and multiple observed exposures where the number of latent variables is specified a priori. We assign one observed exposure as the sentinel marker for each latent variable. The model allows non-sentinel exposures to have complete membership in one latent group, or partial membership across two or more latent groups. MCMC sampling is used to determine latent group partial memberships for the non-sentinel exposures, and estimate all model parameters. We compare the performance of our model to competing approaches in a simulation study and apply our model to inflammatory marker data measured in a large mother-child cohort of the Seychelles Child Development Study (SCDS). In simulations, our model estimated model parameters with little bias, adequate coverage, and tighter credible intervals compared to competing approaches. Under our partial membership model with two latent groups, SCDS inflammatory marker classifications generally aligned with the scientific literature. Incorporating additional SCDS inflammatory markers and more latent groups produced similar groupings of markers that also aligned with the literature. Associations between covariates and birth weight were similar across latent variable models and were consistent with earlier work in this SCDS cohort. Supplementary materials accompanying this paper appear online.
Visceral leishmaniasis (VL) is the most severe disease among other forms of leishmaniasis and results in a fatality in more than 90% of cases if left untreated. It is a zoonotic disease caused by Leishmania donovani and is prevalent in the Indian subcontinent, affecting the population of poor socioeconomic backgrounds. People residing in endemic regions lacking proteins, iron, zinc, and vitamin A in their diet are more prone to develop this opportunist infection into a full-blown disease. The deficiency of a prominent micronutrient vitamin A favors the parasites to develop an infection in the human host, and WHO recommends 200,000 IU doses of vitamin A to VL patients on admission. Additionally, Leishmania entry to the host is favored by cholesterol present in the plasma membrane, and survival inside the host is achieved by utilizing host cholesterol as Leishmania and other trypanosomatids lack de novo synthesis of sterol. However, in our study, we have already reported that a deficit of retinoic acid (RA), a metabolite of vitamin A, favors the parasite to increase their number in L. donovani-infected macrophages by downregulating immune response. Along with this finding, we have also observed the restoration of cellular cholesterol levels in L. donovani-infected macrophages by RA. In this chapter, we have explained the connecting link between cholesterol and RA in visceral leishmaniasis.KeywordsVisceral leishmaniasisCholesterolRetinoic acid
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The majority of autoimmune diseases affect more women than men, suggesting an important role for sex hormones in regulating immune response. Current research supports this idea, highlighting the importance of sex hormones in both immune and metabolic regulation. Puberty is characterized by drastic changes in sex hormone levels and metabolism. These pubertal changes may be what forms the gulf between men and women in sex bias towards autoimmunity. In this review, a current perspective on pubertal immunometabolic changes and their impact on the pathogenesis of a select group of autoimmune diseases is presented. SLE, RA, JIA, SS, and ATD were focused on in this review for their notable sex bias and prevalence. Due to both the scarcity of pubertal autoimmune data and the differences in mechanism or age-of-onset in juvenile analogues often beginning prior to pubertal changes, data on the connection between the specific adult autoimmune diseases and puberty often relies on sex hormone influence in pathogenesis and established sex differences in immunity that begin during puberty.
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THE capacity to down-regulate the production of IL-8 by LPS-activated human polymorphonuclear cells (PMN) has been demonstrated for IL-4, IL-10, and TGF. We compared their relative capacities and further extended this property to IL-13. We report a great heterogeneity among individuals related to the responsiveness of PMN to the IL-4 and IL-13 inhibitory effects while their response to the IL-10 effect was homogenous. The inhibi-tory activities were observed at the transcrip-tional level. IL-8 induction by TNFz was, unlike its induction by LPS, resistant to the inhibitory effects of IL-IO, IL-4, IL-13 and TGF. Furthermore , IL-10 and IL-4 inhibitory activity were less effective when TNFz was acting synergistically with LPS to induce IL-8 production by PMN. LPS-induced cell-associated IL-8, detected in the PMN cultures, could be marginally inhibited by IL-4 and IL-10. Altogether, our data demonstrate that IL-13 is able to inhibit LPS-induced IL-8 production by human PMN, although IL-IO remains the most active anti-inflammatory cytokine. Despite the capacity of IL-4, IL-IO, and IL-13 to limit the production of TNFz-induced IL-8 in a whole blood assay, none was able to inhibit this production when studying isolated human polymorphonuc-lear cells.
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We used IL-6 knock-out (KO) mice to evaluate a possible role for IL-6 in the pathogenesis of splanchnic artery occlusion shock (SAO). SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk, followed by release of the clamp. There was a marked increase in the peroxynitrite formation in the plasma of the SAO-shocked IL-6 wild-type (WT) mice after reper- fusion. Immunohistochemical examination demon- strated a marked increase in the immunoreactivity to nitrotyrosine in the necrotic ileum in shocked IL-6 WT mice. SAO-shocked WT mice developed a significant increase of tissue myeloperoxidase (MPO) and malondialdehyde (MDA) activity and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortal- ity (0% survival). Reperfused ileum tissue sections from SAO-shocked WT mice showed positive stain- ing for P-selectin. Little specific staining was ob- served in sham-WT mice. Staining of ileum tissue obtained from sham-operated WT mice with anti- ICAM-1 antibody showed weak but diffuse staining, demonstrating that ICAM-1 is constitutively ex- pressed. However, after SAO shock the staining intensity increased substantially in the ileum sec- tion from WT mice. Intensity and degree of P- selectin and ICAM-1 were markedly reduced in tissue section from SAO-shocked IL-6 KO mice. SAO-shocked IL-6 KO mice also show significant reduction of neutrophil infiltration into the reper- fused intestine, as evidenced by reduced MPO activity, improved histological status of the reper- fused tissues, reduced peroxynitrite formation, re- duced MDA levels, and improved survival. In vivo treatment with anti-IL-6 significantly prevents the inflammatory process. Our results clearly demon- strate that IL-6 plays an important role in ischemia and reperfusion injury and allows the hypothesis that inhibition of IL-6 may represent a novel and possible strategy. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil-mediated cellular injury. J. Leukoc. Biol. 66: 471-480; 1999.
nterleukin-8 (IL-8) is produced by many cell types upon stimulation with bacterial products or inflammation-associated cytokines such as tumor necrosis factor-alpha and IL-1. Interferons (IFNs) represent another group of cytokines that are induced by similar stimuli in inflammatory reactions. We show now that type-I IFNs are potent inhibitors of IL-8 expression in vitro and in vivo. A significant reduction of both secretion of IL-8 protein and accumulation of IL-8 mRNA in vitro was observed in several cell types comprising peripheral blood mononuclear cells (PBMNC) from healthy donors and from patients with chronic myelogenous leukemia (CML), the myelomonocytic cell line THP-1, and bone marrow (BM) stromal cells as a representative model for BM microenvironment. By contrast, in lipopolysaccharide-stimulated polymorphonuclear phagocytes IFN failed to suppress IL-8 expression. In untreated patients with CML, a constitutive expression of IL-8 mRNA was detected in freshly isolated PBMNC that was markedly reduced 5 hours after therapeutic application of IFN-alpha. The mechanism of IL-8 downregulation was studied more in detail in the THP-1 cell line. The experiments showed that de novo protein synthesis was not required for the inhibitory effect. RNA decay analysis and nuclear run-on assays suggest that in THP-1 cell line the inhibition of IL-8 expression is predominantly regulated at the posttranscriptional level.
The T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Th1 lymphocytes and macrophages (M phi). The nonobese diabetic mouse strain (NOD/Shi) develops a M phi and T cell-dependent autoimmune diabetes that closely resembles human insulin-dependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-10 positive I-A beta g7/g7, I-E- mice in first (N2) and second (N3) generation backcrosses between IL-10 transgenic BALB/c mice and (NOD/Shi) mice. None of the IL-10 negative major histocompatibility complex-identical littermates were diabetic at this age. Furthermore, diabetes developed in 33% of I-A beta g7/d, I-E+ N3 mice in the presence of IL-10 before the mice were 10 wk old. Our findings support the notion that IL-10 should not simply be regarded as an immunoinhibitory cytokine, since it possesses powerful, immunostimulatory properties as well. Furthermore, our observations suggest that beta cell destruction in NOD mice may be a Th2-mediated event.
A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.
The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.
The aim of this study was to determine the effect of interleukin-4 (IL-4) and interleukin-10 (IL-10) on interleukin-8 (IL-8) release from endothelial cells. Confluent monolayers of human umbilical vein endothelial cells (HUVECs) were incubated in the absence or presence of 10 ng/ml of bacterial lipopolysaccharide (LPS), with 5% human AB serum and recombinant human IL-4 or IL-10 over a dose range from 50 fg/ml to 50 ng/ml (final concentration). IL-4 and IL-10 had no effect on HUVEC IL-8 release in the absence of LPS. In the presence of LPS, IL-4 and IL-10 enhanced IL-8 release by approximately 300% compared with LPS-stimulated cells alone, IL-8 release increasing from 2594 +/- 493 pg/ml (no IL-4 or IL-10) to 7892 +/- 320 pg/ml (IL-4, 5 pg/ml; p = 0.001) and 8359 +/- 712 pg/ml (IL-10, 50 pg/ml; p = 0.002). IL-8 release in response to IL-4 or IL-10 plateaued above 5 and 50 pg/ml, respectively. This study suggests that IL-4 and lL-10 may be involved in the complex regulation of endothelial cell cytokine production during the response to endotoxin.
In vitro, expression of E-selectin is largely restricted to endothelial cells activated by inflammatory cytokines. Under activated conditions, cytokines such as interleukin (IL) 10, released by keratinocytes in large quantities, may also increase the expression of E-selectin on the dermal microvasculature. The aim of the present study was to investigate the expression of E-selectin on cultured human dermal microvascular endothelial cells (HDMEC) isolated from neonatal foreskins when exposed to IL-10. Expression of E-selectin was determined by immunofluorescence microscopy, FACS analysis, an HL-60 cell-binding assay, and quantitative polymerase chain reaction (PCR) analysis. For comparison with large blood vessel cells, the expression of E-selectin on human umbilical vein endothelial cells (HUVEC) was also determined in parallel by FACS and reverse transcriptase-PCR analysis under identical conditions. These studies demonstrate that IL-10 induces the expression of E-selectin on both HDMEC and HUVEC and that the level of expression of HDMEC is comparable with that induced by IL-1 beta and tumor necrosis factor-alpha. When HL-60 cells are incubated with HDMEC pretreated with IL-10, a consistent increase in adherence of HL-60 to endothelial cells is observed. This adherence was found to be mediated by L-selectin. PCR analysis and the quantification of E-selectin cDNA by a novel, highly sensitive and specific PCR-immunoassay demonstrate the induction of E-selectin mRNA at the transcriptional level. The induction of the expression of E-selectin by IL-10 on HDMEC may provide additional insights into the pathogenic mechanism of neutrophil accumulation at the site of inflammation in inflammatory skin diseases.