Cytokine‐mediated inflammatory hyperalgesia limited by interleukin‐4

Cunha, Fernando; Poole, Stephen; Lorenzetti, Berenice B.; Veiga, Fabiane H.; Ferreira, S. H.

doi:10.1038/sj.bjp.0702266

Cited by 129 publications

(75 citation statements)

References 53 publications

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“…Discussion IL-33 is a newly discovered cytokine that acts through the ST2/IL1RAcP (IL-1 receptor accessory protein) receptor complex (1, 20,21) and is closely associated with Th2-type immune functions (1, 7,8) and mast cell activation (1, 22, 23). We have previously demonstrated that Th1 cytokines induce hypernociception, whereas Th2 cytokines such as IL-4 and IL-13 inhibit hypernociception (24)(25)(26)(27). Thus, data presented here showing a pronociceptive role of IL-33 may seem contraintuitive.…”

Section: Il-33 Inducesmentioning

confidence: 53%

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

Verri

Guerrero

Fukada

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

163

155

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cytokines ͉ inflammation ͉ pain ͉ rheumatoid arthritis ͉ hyperalgesia I L-33 is a recently described member of the IL-1 family that includes IL-1␤ and IL-18. Like IL-1␤ and IL-18, IL-33 was found to have strong immunomodulatory functions (1). However, unlike IL-1␤ and IL-18, which mainly promote T-helper 1 (Th1)-associated responses, IL-33 predominantly induces the production of Th2 cytokines (IL-5 and IL-13) and increases the levels of serum Ig. IL-33 was recently found to be the ligand for the orphan receptor ST2 (1), which also is known as T1, DER4, or Fit (2-5). The interaction between IL-33 and ST2 was sufficient to trigger the activation of NF-B and all three MAPKs (p38, ERK1/2, and JNK1/2) in a mast cell line. In vitro, IL-33 enhanced IL-5 and IL-13 production by polarized Th2, but not Th1, cell lines. In addition, the administration of human IL-33 into naïve mice provoked innate type 2 cytokine, IgE production, and eosinophilia (1).The ST2 gene encodes two isoforms of ST2 protein: ST2L, a transmembrane form, and soluble ST2 (sST2) (6), a secreted form that can serve as a decoy receptor of IL-33 (1). ST2L is preferentially expressed on Th2, but not Th1, cells (7,8) and can profoundly suppress innate and adaptive immunity (9, 10). ST2 also is expressed on mast cells, macrophages, and fibroblasts. We have previously shown that sST2 is a potent inhibitor of collagen-induced arthritis in mice (11), suggesting that the IL-33-ST2 signaling pathway is a key mediator of rheumatoid arthritis (RA). Arthritic lesions are accompanied by movement limitation secondary to articular hyperalgesia, and there is consistent evidence that cytokines induce hypernociception (hyperalgesia and/or allodynia in experimental animals) (12-15). Therefore, we have investigated the role of IL-33 in immune inflammatory hypernociception in mice.We report here that IL-33 is a key mediator of methylated BSA (mBSA)-induced cutaneous and articular mechanical hypernociception. IL-33 mediates hypernociception via the sequential TNF␣ 3 IL-1␤ 3 IFN␥ 3 endothelin 1 (ET-1) 3 prostaglandin (PG) E 2 signaling cascade. These results therefore reveal a hitherto uncharacterized important pathway of antigen-induced hypernociception normally associated with Th1 response. Furthermore, our results suggest that IL-33 may be a potential therapeutic target for immune inflammatory hypernociception. Results IL-33Mediates Cutaneous Mechanical Hypernociception. IL-33 intraplantar (i.pl.) injection induced mechanical hypernociception in mice in a dose-and time-dependent manner (Fig. 1A). The response was significant from 0.5 h, reaching maximal response between 3 and 5 h, decreasing thereafter to a control level at 48 h. The IL-33-induced hypernociception was restricted to the ipsilateral paw at the doses used (data not shown), indicating a local effect. A 70 ng per paw dose and readout at 3 h were chosen for subsequent experiments. IL-33-induced cutaneous hypernociception was significantly inhibited by the treatment with sST2-Fc, but not by the Fc control (Fig. 1B...

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Section: Il-33 Inducesmentioning

confidence: 53%

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

Verri

Guerrero

Fukada

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

163

155

View full text Add to dashboard Cite

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“…Identical responses were obtained in vitro on macrophage cultures. Moreover, the hyperalgesic response to IL-1␤ was inhibited by 30 to 74% by intraplantar IL-4 when IL-4 was injected 12 h before IL-1␤ whereas it had no effect when it was administered 30 min before IL-1␤ (Cunha et al 1999). Exposure of murine peritoneal macrophages to murine IL-4 for 16 h before stimulation with LPS inhibited LPS-induced production of prostaglandin E 2 (PGE 2 ) but not of IL-1␤.…”

Section: Discussionmentioning

confidence: 97%

“…In particular, sublethally infected mice given IL-4 at the time of infection responded to this treatment with increased mortality and overproduction of TNF-␣ (Giampietri et al 2000). Moreover, IL-4 administered 30 min before inhibited the hyperalgesia induced by bradykinin and TNF-␣ but not by IL-1␤ (Cunha et al 1999). In vitro, IL-4 failed to inhibit LPS-induced production of IL-1␤ in cocultures of rat microglia and astrocytes (Ledeboer et al 2000) and IL-6 in mouse primary astrocytes , and it was able to enhance TNF-␣ (Giampietri et al 2000) and IL-6 production (Pousset et al 1999) under some conditions.…”

Section: Discussionmentioning

confidence: 98%

“…Exposure of murine peritoneal macrophages to murine IL-4 for 16 h before stimulation with LPS inhibited LPS-induced production of prostaglandin E 2 (PGE 2 ) but not of IL-1␤. In the early phase of the hyperalgesic response, IL-4 inhibited the production of the hyperalgesic cytokines TNF-␣ and IL-1, whereas in the later phase of the hyperalgesic response, IL-4 inhibited COX-2 enzymes, since IL-4 given 12 h before IL-1␤, inhibited the hyperalgesic effect of IL-1␤ and the release of PGE 2 by murine macrophages stimulated in vitro with LPS (Cunha et al 1999). The anti-inflammatory effects of IL-4 can be explained by a decrease in the production of pro-inflammatory cytokines, certainly via inhibition of the nuclear transcription factor NFkappaB (Chao et al 1993;Giampietri et al 2000;.…”

Section: Discussionmentioning

confidence: 99%

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Dual Effect of Central Injection of Recombinant Rat Interleukin-4 on Lipopolysaccharide-Induced Sickness Behavior in Rats

Bluthé

Lestage

Rees

et al. 2002

Neuropsychopharmacology

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Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) has profound depressive effects on behavior that are mediated by the inducible expression of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor ␣ (TNF), in the brain. To assess the regulatory effects of the anti-inflammatory cytokine IL-4 on LPS-induced sickness behavior, rats injected intra-peritoneally (i.p.) with LPS were administered intracerebroventricularly (i.c.v.) with When an organism becomes sick during the course of an infection, several changes occur, which are mediated by the central nervous system (CNS). These changes include regulated increases in body temperature, sleep, activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, decreases in locomotor activity, feeding, drinking, and social interactions, and alterations in brain neurotransmitters. They are due to the release of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-␣ ) by activated monocytes and macrophages Dinarello 2000;Gabay and Kushner 1999;Krueger et al. 1999;Mulla and Buckingham 1999;Rothwell 1997;Turrin and Plata-Salaman 2000). The same effects can be obtained by systemic administration of the cytokine-inducer lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria (Cabrera et al. 2000;Francis et al. 2000;Lacosta et al. 1999;Ma et al. 2000;MohanKumar et al. 2000;Roth and de Souza 2001;Swiergel and Dunn 1999;Yirmiya 1996;Yirmiya et al. 2001). Peripherally released cytokines act on the brain by inducing the expression and release of cytokines in the central nervous system (Eriksson et al. 2000;Konsman et al. 1999;Layé et al. 2000;Quan et al. 2000). LPS induces the expression of not only pro-inflammatory but also anti-inflammatory cytokines such as IL-10 and IL-13 in the brain (Wong et al. 1997 Laman et al. 1998;Liedtke et al. 1998; Woodroofe and Cuzner 1993). Anti-inflammatory cytokines have the ability to suppress the synthesis of IL-1, TNF, and other cytokines in peripheral immune and non-immune cells (Dinarello 1997;Marie and Cavaillon 1997).There has been a recent surge of interest in the behavioral effects of cytokines in neuropsychopharmacology. Several reasons account for that, including the fact that cytokine-induced sickness behavior is not the result of weakness and physical debilitation but appears to be the expression of a previously unrecognized motivational state that is triggered by peripheral immune stimuli and reorganizes the organism's priorities (Dantzer 2001). In addition, the possibility of an intersection between sickness behavior and depression has raised new and important issues in psychopathology.If sickness behavior is the ineluctable result of the brain action of those proinflammatory cytokines that are released at the periphery during the course of an innate immune response or even in response to exteroceptive stressors, it becomes important to find out how this behavior is regulated. The production and ac...

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“…Bien que peu d'études aient recherché l'efficacité de telles stratégies sur l'hyperalgésie, leurs résultats semblent prometteurs. Dans les modèles de douleur inflammatoire comme neurologique, l'hyperalgésie décrite est atténuée par l'application locale (au site d'inflammation ou de lésion) d'IL-10 ou d'IL-4 [19,20], ou encore par l'introduction dans l'espace intrathécal de vecteurs plasmidiques ou adé-noviraux permettant la production d'IL-2 ou d'IL-10 [21,22]. Le contrôle ciblé de leur production et de leur libération par les cellules gliales spinales activées pourrait repré-senter une voie thérapeutique dans le traitement des douleurs chroniques chez l'homme.…”

Section: Cytokines Et Thérapie Génique De La Douleurunclassified

Inflammation et douleur : thérapie génique expérimentale

et al. 2004

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La douleur aiguë, douleur-symptôme, peut être considérée par le clinicien (et perçue par l'organisme) comme un signal d'alarme utile. En revanche, la douleur chronique, douleur-maladie, persistant au cours du temps, ne peut être simplement assimilée à une douleur aiguë qui perdure. Elle est associée à de profondes altérations des systèmes neuronaux impliqués dans le traitement de l'information nociceptive 1 . Ces changements affectent aussi bien les premiers maillons intervenant dans la genèse et le transfert des messages nociceptifs (c'est-à-dire les neurones sensoriels primaires), que la corne dorsale de la moelle épinière, où ces neurones établissent leurs premiers relais synaptiques, et certaines structures cérébrales (Figure 1). Médiateurs chimiques et douleurUn grand nombre de médiateurs chimiques jouent un rôle dans l'induction, la transmission et la modulation des messages nociceptifs. Lors d'une inflammation péri-phérique, des molécules synthétisées et libérées dans le foyer inflammatoire, comme les prostaglandines, la bradykinine, la sérotonine, certaines cytokines et le NGF (nerve growth factor), agissent directement sur les terminaisons des neurones sensoriels primaires pour les stimuler, les sensibiliser à l'action d'autres molécules, ou encore modifier leur phénotype. C'est ainsi que l'expression de nombreux neuropeptides tels que la substance P (SP), le CGRP (calcitonin gene-related peptide), les peptides opioïdes ou la galanine, est altérée au sein même de ces neurones et/ou dans des neurones spinaux. De plus, la synthèse, le transport et la densité des récepteurs de certaines de ces molécules sont profondément modifiés (Figure 1). Cytokines pro-inflammatoires et douleur > Récemment, plusieurs équipes ont montré l'intérêt potentiel des transferts de gènes, à l'aide de divers vecteurs, dans des modèles animaux de douleurs chroniques. Le transfert de gènes codant pour des précurseurs de peptides opioïdes endogènes, conduisant à la production -dans la moelle épinière ou les neurones sensoriels primaires -de grandes quantités de peptides physiologiquement actifs qui en dérivent, se traduit par une diminution marquée des douleurs chroniques d'origine inflammatoire ou neurologique. D'autres molécules, comme les cytokines, impliquées dans l'induction ou la persistance des douleurs, représentent des cibles potentielles de ces approches. Bien que des progrès importants aient été réalisés dans le développement des vecteurs utilisés, leur innocuité reste à démontrer chez l'homme avant d'envisager la thérapie génique des douleurs chroniques rebelles aux traitements actuellement disponibles. Article disponible sur le site

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Cytokine‐mediated inflammatory hyperalgesia limited by interleukin‐4

Cited by 129 publications

References 53 publications

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

Dual Effect of Central Injection of Recombinant Rat Interleukin-4 on Lipopolysaccharide-Induced Sickness Behavior in Rats

Inflammation et douleur : thérapie génique expérimentale

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