ISSN 0145-5680
`
`June
`Vol. 47/ No. 4 2001
`
`Editor
`
`K.-J. Halbhuber, Jena, Germany
`
`\CELLULAR
`AND
`MOLECULAR
`BIOLOGY
`
`IND MOLECULA®
`
`CYTOKINES AND CHEMOKINES
`
`Guest Editors
`P. Bongrand, Marseille
`G. Kaplansky, Marseille
`
`®
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`ms
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`\S
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`As)
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`HEALTH SCIENCES LIBRA
`UNIVERSITY OF WISCONSIN
`AUG 0 8 2001
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`Cellular and
`Molecular Biology«
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`Editor-in-Chief
`
`K.-J. Halbhuber
`Institute ofAnatomy I, Friedrich-Schiller University, Jena, Germany
`
`Associate Editor, U.S.A. and Canada
`
`R.F. Ochillo
`Graduate School, Morgan State University, Baltimore, Maryland, USA
`
`Associate Editor, Asia
`
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`C.A.R.D., Kumamoto University, Kumamoto, Japan
`
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`K. Konig
`Institute ofAnatomy II, Friedrich-Schiller University, Jena, Germany
`
`Guest Editors
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`P. Bongrand
`G. Kaplansky
`Laboratoire d'Immunologie, INSERM U 387, Marseille, France
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`

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`CELLULAR AND MOLECULAR BIOLOGY™ |
`
`2001, Volume 47, Number 4
`
`2S me lg
`
`CYTOKINES AND CHEMOKINES
`
`Content
`
`569 Foreword: Cytokines and chemokines
`G. KAPLANSKY and P. BONGRAND
`
`575 Receptor dimerization: a key step in chemokine signaling
`M. MELLapo, A.J. ViILA-Coro, C. MARTINEZ-A. and J.M. RODRIGUEZ-FRADE
`
`583
`
`The soluble IL-6 receptors: serum levels and biologicalfunction
`F.A. MONTERO-JULIAN
`
`599 Chemokines and lymphocytes: The role ofchemokines andtheir receptors in the immune system
`H. HaseGawa and S. FUJITA
`
`609
`
`JInterferon-a in inflammation and immunity
`A. KAser and H. TILG
`,
`
`619 TNF and TNFRbiology in health and disease
`M.F. McDERmoTTr
`
`637 Role ofinterleukin-13 in innate and adaptive immunity
`J.O. BRUBAKER and L.J. MONTANER
`
`653
`
`The impact of chemokine receptor conformational heterogeneity on HIVinfection
`F, BARIBAUD and R.W. Doms
`
`661 Mediators ofinflammation and acute phase response in the liver
`K.L. STREETZ, T. WUSTEFELD, C. KLEIN, M.P. MANNS and C. TRAUTWEIN
`
`675 Cytokines in rheumatoid arthritis: Is it all TNF-a?
`P. MIOssEC
`
`679 Cytokines, from atopy to asthma: The Th2 dogmarevisited
`A. MAGNAN,S. BONIFACE, L. MELY, S. ROMANET, E. MAMESSIER and D. VERVLOET
`
`689 Breach ofIL-12 monopoly in theinitiation of Type 1 immunity to intracellular infections: IL-12 is not requiredfor host
`defense againstviral infections
`Z. XING
`
`695 Pro- versus anti-inflammatory cytokines: myth orreality
`J.-M. CAVAILLON
`
`703 Characterization ofan IL-2 mimetic with therapeutic potential
`R. ECKENBERG,T. Rose,J.-L. MOREAU, R. WEIL, F. GESBERT, S. DuBots, D. TELLO, M. Bossus, H. Gras, A. TARTAR, J. BERTOGLIO,
`S. CHouais, Y. JACQUES, P.M. ALzari and J. THEZE
`
`Indexed/Abstracted in:
`
`Current Contents, Index Medicus, MEDLINE,
`BIOSIS Database, SUBIS,PASCAL/CNRS Database,
`Cam. Sci. Abstr.,CAB Inter., Chem. Abstr. Service,
`RIS in References Update
`,
`Published by C.M.B. ASSOCIATION
`Editorial Office: 1, Avenue du Pavé Neuf
`F-93160 Noisy-le-Grand (France)
`
`ISSN 0145-5680
`CMBIDI 47(4) 568-708 (2001)
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` This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Cellular and Molecular Biology™47 (4), 695-702
`Printed in France.
`
`0145-5680/01
`2001 Cell. mol. Biol.”
`
`Review
`
`PRO- versus ANTI-INFLAMMATORY CYTOKINES:
`MYTH OR REALITY
`
`Jean-Marc CAVAILLON
`
`Department of Physiopathology,Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France
`E-mail: jmcavail@pasteurfr
`
`Received November8, 2000; Accepted November17, 2000
`
`Abstract - Inflammationis characterized by aninterplay 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-y), IL-12, IL-18
`and granulocyte-macrophage colonystimulating factor are well characterized as pro-inflammatory cytokines whereas IL-4, IL-10,
`IL-13, IFN-a and transforming growth factor-B are recognized as anti-inflammatory cytokines. In this review, we point out that
`this classification is far too simplistic and we provide numerous examplesillustrating that a given cytokine may behaveas a pro-
`as well as an anti-inflammatory cytokine. Indeed, the cytokine amount, the nature ofthe 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
`
`A TOO SIMPLISTIC DICHOTOMY
`
`as an interplay between pro- and anti-inflammatory actors.
`INTRODUCTION
`Indeed, they are far more complex!In this short review
`we will provide some examples whichillustrate the fact
`Cytokines play an important
`role during the
`that each of these cytokines offers a "half angel - half
`inflammatory
`process.
`Two
`cytokines,
`namely
`devil" aspect and none can be simply labelled either "pro"
`interleukin-1 (IL-1) and tumor necrosis factor (TNF)
`or "anti".
`orchestrate the inflammatory response and initiate a
`cascade ofmediators whichare 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-y) 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-c.) and transforming growth factor-6 (TGF-B)
`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-lra) 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 inflammationare not as simplistic
`
`René Magritte, the surrealistic Belgium artist, painted
`a pipe on a picture and wrote "Ceci n’est pas une pipe"
`(This is not apipe). Itis becoming more and morefrequent
`to find reports reminiscentofthis 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-y
`(either by anti-IFN-y antiserum or by using IFN-y receptor
`
`695
`
`

`

`696
`
`J.-M. Cavaillon
`
`knock-out mice) resulted in an accelerated onset of the
`disease (70). Theseresults suggested that IFN-y, instead of
`being a pro-inflammatory cytokine, wasrather 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 pancreaticislets (52,74). Also, IL-10
`treatment accelerates allograft rejection ofislet 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 adenocarcinomacells expressing IL-10,
`Di Carlo etal. (20) showedthat 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 ofVCAM-1 and ELAM-1 adhesion molecules
`and an enhanced recruitment ofleukocytes as comparedto
`mice receiving the parent adenocarcinoma. Thisparallels
`the fact that IL-10 induces E-selectin expression on small
`and large blood-vessel endothelial cells (71).
`Wewill now review few parameters which influence
`the behavior of the different cytokines and may explain
`why, depending upon thesituation, both pro- and anti-
`inflammatory properties can be described for the same
`mediators.
`
`THE AMOUNTOF 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 amountof a given cytokine clearly influencesits
`
`properties. The best example is given with TGF-B (9): in
`addition to its role in controlling inflammation, TGF-6
`restrains cell proliferation and controls turnover of the
`extracellular matrix. At high concentration, TGF-6
`suppressescell proliferation and stimulates the production
`of pathological amounts of extracellular matrix (fibrosis)
`whereas at low levels, TGF-B 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
`wereinfluenced by the amountofthis cytokine usedin the
`experimental model. Low doses were found to induced
`angiogenesis whereashigh concentrations were associated
`with an inhibition of angiogenesis (23). Moreover, in an
`elegant experimental model of arthritis induced by the
`injection ofacidified 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 wasessentially 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 inducedcirculating 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 astarget cells. There
`are numerous examples which illustrate that the story
`might be completely different with othertarget cells. Thus,
`IL-10 was first
`identified and defined as a cytokine
`capable to repress the production of IFN-y by Th1 clones
`(25), but more recently it was demonstrated that IL-10
`enhanced the production of IFN-y by NK cells (63),
`increased the intracellular expression of IFN-y and IL-2 in
`CD8* 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-o. which limits this production by LPS-
`activated peripheral blood mononuclear cells and by TNF-a.-
`stimulated bone marrow stroma cells but which is
`inefficient when acting on LPS-activated, neutrophils (2).
`While IL-13 diminishes chemokine production by
`
`

`

`Pro- versus anti-inflammatory cytokines
`
`697
`
`activated macrophages,it induces the synthesis of MCP-1
`by endothelial cells (29). While TGF-81 limits the
`production of IL-la 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 bybone marrow derived macrophagesandosteoclasts
`(7,65). Acting on bone marrow derived mastcells, IL-10
`synergized with c-kit ligand and LPS to increase the
`production of cyclooxygenase type 2 and PGD2 aswellas
`the expression of IL-6 mRNA(51). When addressing the
`regulation of
`IL-1f-induced IL-6 production by
`astrocytes, Pousset et al. (55) showed that IL-10 but
`neither IL-4 nor dexamethasone possessed inhibitory
`properties.
`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-f (22).
`Discrepancies have also been reported in termsofthe
`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 humanepithelial cells (64)
`and favors the expression of VCAM-1 on endothelial
`cells, allowing the adherence ofbasophils 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
`ACTIVATING SIGNAL
`
`The inhibitory capacity of the so-called anti-
`inflammatory cytokines may also depend onthe 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-a. (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-a 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 ofthe production ofvarious chemokinesled to
`a rather complex pattern. Thus, it has been reported that
`IL-4 did not affect the production of RANTESby IFN-y-
`activated human monocytes whereas it was capable to
`mcrease this production when the cells were activated
`with TNF-c (44). In the presence of IL-2, the production
`of IFN-y by splenocytes from scid mice was unchanged
`when the cells were cultured with IL-12 and TNF-a
`whereas this production was greatly inhibited when the
`cells were
`activated with
`heat-killed Listeria
`monocytogenes (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 ofmonocytes 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 oftissue factor on the surface
`of endothelial cells activated with LPS, whereas there was
`no inhibition when IL-18 was used asthe triggering agent
`(32). A totally different pattern was obtained whentissue
`factor expression was analyzed on the surface of
`monocytes.
`
`THE NATURE OF THE
`PRODUCED CYTOKINE
`
`the
`The capacity of a given cytokine to inhibit
`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-la, IL-1 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-o (11). We reported that in whole blood
`
`

`

`698
`
`J.-M. Cavaillon
`
`samples activated by heat-killed Streptococcus pyogenes,
`IL-13 inhibited the production of IL-8 but was unable to
`modify that of TNF-o. (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 production
`was reduced whereas the TNF-a production was
`unaffected (31). Studying IL-lc-activated human bone
`matrow stromacells, IL-4 was also shown to enhancethe
`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
`macrophagesinhibits the production of IL-8 and MIP-lo
`but favors the release of MCP-1, RANTES, AMAC-1 and
`C10. A completely different profile might be found when
`considering anothertarget 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-y
`which enhancesthe production of IP-10 and RANTESby
`macrophagesbutinhibits the production of GRO, MIP-1a,
`MIP-18 and AMAC-1.
`
`THE TIMING
`
`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-a,
`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
`systemic Pseudomonas aeruginosa infection, Giampietri
`et al. (28) demonstrated that a 24 hr pre-treatment of mice
`with IL-4 wasprotective when high number of CFU were
`injected whereas when injected only 1 hr before the
`bacterial challenge with a lower number ofCFU,IL-4 was
`deleterious.
`In the first case enhanced survival was
`associated with a reducedlevelof 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 keyrole in the
`nature of the signals delivered to the cells. For example,
`TNF and INF-y used simultaneously have nosignificant
`effect on the production of NO by rat bone marrow-
`derived macrophages. In contrast, IFN-y primes thecells
`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-y 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-6
`whereas IL-10 had noinhibitory 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-y, produced significant amounts of IL-12
`whereaslow or no production wasobtained with cells pre-
`treated with either TNF or TNF + IFN-y.
`
`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. Wereported 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 performedonplastic (i.e. with adherence
`of monocytes) the classical inhibitory activity of IL-10
`wasfound(1). Altogether, these results indicate that IL-10-
`induced modulation of cytokine production depends on
`the 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 JL-13 increased the
`
`

`

`|
`
`Pro- versus anti-inflammatory cytokines
`
`699
`
`inflammatory process, suggesting that endogenous IL-13
`restrained inflammation (41). In contrast, transgenic mice
`over-expressing IL-13
`in the
`lungs
`showed an
`inflammatory mononuclearinfiltrate, eosinophils around
`airways and in parenchyma, an airway epithelial
`hypertrophy, a goblet cell hyperplasia, a hyperproduction
`of mucus anda 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).
`Wealready mentionedthe protective role of IFN-y ina
`model of collagen-induced arthritis and the accelerated
`onset of the disease in IFN-y-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
`IFN-y receptor knock-out animals (49). The authors
`demonstrated that on one hand IFN-y induced pro-
`inflammatory cytokines such as TNF and IL-12, on the
`other hand,
`in the model using CFA (i.e. associating
`Mycobacteria), IFN-y had a beneficial role by restraining
`both the expansion of hematopoietic process and the
`number of macrophages, a major source of pro-
`inflammatory cytokines.
`
`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
`mentionedthat 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 presenceof its soluble receptor whichis
`naturally found in plasma (58). Deleterious activities of
`IL-6 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
`inflammatory responses (14,15).
`
`CONCLUSION
`
`Wehaveto admit that dogmaoftenresult from an over-
`simplification of the described phenomena. Accordingly,
`dogma are made to be broken!
`It appears that
`the
`inflammatory response is an extremely complexinterplay
`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
`knowngenetic 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 termsoftarget
`cell reactivity in response to cytokine signaling (5). This
`individual heterogeneity has also to be considered when
`addressing the inflammatory response.
`
`REFERENCES
`
`1. Adib-Conquy, M., Petit, A-F., Marie, C., Fitting, C. and Cavaillon,
`J.-M., Paradoxical priming effects ofIL-10 on cytokine production.
`Intn. Immunol. 1999, 11: 689-698.
`2. Aman, M.J., Rudolf, G., Goldschmitt, J., Aulitzky, W.E., Lam,C.,
`Huber, C. and Peschel, C., Type-I interferons are potent inhibitors
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