IL-9 Protects Mice from Gram-Negative Bacterial Shock: Suppression of TNF-α, IL-12, and IFN-γ, and Induction of IL-10

Grohmann, Ursula; Snick, Jacques Van; Campanile, F.; Silla, Silvia; Giampietri, A; Vacca, Carmine; Renauld, Jean‐Christophe; Fioretti, Maria Cristina; Puccetti, Paolo

doi:10.4049/jimmunol.164.8.4197

Cited by 61 publications

(46 citation statements)

References 42 publications

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“…Firstly, prophylactic administration of IL-9 protects mice from death in a model of sepsis induced by i.v. injection of Pseudomonas aeruginosa (13). This protective effect, also observed with IL-4, was associated with a strong reduction of serum levels of TNF-␣, IL-12/p40, and IFN-␥ induced by the bacteria or LPS injection, and with a dramatic increase of IL-10.…”

Section: Il-9 Inhibits Oxidative Burst and Tnf-␣ Release In Lipopolysmentioning

confidence: 64%

“…The present finding that mononuclear phagocytes are regulated by IL-9 may be more specifically relevant to inflammatory disorders, such as sepsis, in which monocyte/macrophage activation plays a central role. Interestingly, it was recently shown that administration of IL-9 prevented mortality in mice challenged with P. aeruginosa (13). Moreover, this beneficial effect was dependent on a prophylactic administration of IL-9 because no improvement in survival was observed when rIL-9 was injected concomitantly or after the infectious challenge.…”

Section: Discussionmentioning

confidence: 99%

“…In additional experiments, we showed that in contrast with the down-regulation of IL-10 release in monocytes, IL-10 is upregulated in supernatants from unseparated blood mononuclear cells treated with IL-9, and not in lymphocytes (data not shown), suggesting an interplay between monocytes and lymphocytes in cocultures. A protection of mice from lethal endotoxemia was shown with other Th2 cytokines, namely IL-4, IL-10, and IL-13 (13,(41)(42)(43)(44); and was associated with a reduction of TNF-␣ production. Th2 cytokine-mediated protection in in vivo models of exaggerated inflammatory response is thought to be related to the capacity observed in vitro of these cytokines to deactivate mononuclear phagocytes.…”

Section: Discussionmentioning

confidence: 99%

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IL-9 Inhibits Oxidative Burst and TNF-α Release in Lipopolysaccharide-Stimulated Human Monocytes Through TGF-β

Pilette¹,

Ouadrhiri²,

Snick

et al. 2002

The Journal of Immunology

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IL-9 is a Th2 cytokine that exerts pleiotropic activities on T cells, B cells, mast cells, hematopoietic progenitors, and lung epithelial cells, but no effect of this cytokine has been reported so far on mononuclear phagocytes. Human blood monocytes preincubated with IL-9 for 24 h before LPS or PMA stimulation exhibited a decreased oxidative burst, even in the presence of IFN-γ. The inhibitory effect of IL-9 was specifically abolished by anti-hIL-9R mAb, and the presence of IL-9 receptors was demonstrated on human blood monocytes by FACS. IL-9 also down-regulated TNF-α and IL-10 release by LPS-stimulated monocytes. In addition, IL-9 strongly up-regulated the production of TGF-β1 by LPS-stimulated monocytes. The suppressive effect of IL-9 on the respiratory burst and TNF-α production in LPS-stimulated monocytes was significantly inhibited by anti-TGF-β1, but not by anti-IL-10Rβ mAb. Furthermore, IL-9 inhibited LPS-induced activation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases in monocytes through a TGF-β-mediated induction of protein phosphatase activity. In contrast, IL-4, which exerts a similar inhibitory effect on the oxidative burst and TNF-α release by monocytes, acts primarily through a down-regulation of LPS receptors. Thus, IL-9 deactivates LPS-stimulated blood mononuclear phagocytes, and the mechanism of inhibition involves the potentiation of TGF-β1 production and extracellular signal-regulated kinase inhibition. These findings highlight a new target cell for IL-9 and may account for the beneficial activity of IL-9 in animal models of exaggerated inflammatory response.

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Section: Il-9 Inhibits Oxidative Burst and Tnf-␣ Release In Lipopolysmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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IL-9 Inhibits Oxidative Burst and TNF-α Release in Lipopolysaccharide-Stimulated Human Monocytes Through TGF-β

Pilette¹,

Ouadrhiri²,

Snick

et al. 2002

The Journal of Immunology

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“…IL-9 has been shown to protect mice from gram-negative bacterial shock, and this effect was correlated with the down-regulation of tumor necrosis factor alpha, IL-12, and gamma interferon production and with the upregulation of IL-10 production (21). The generation of transgenic mice overexpressing IL-9 has suggested a critical role for this cytokine in a variety of immunological responses, including intestinal mastocytosis and enhanced resistance to nematode infection (14,15).…”

Section: Among the Distinct Cd4mentioning

confidence: 99%

Modulation of Intestinal Muscle Contraction by Interleukin-9 (IL-9) or IL-9 Neutralization: Correlation with Worm Expulsion in Murine Nematode Infections

et al. 2003

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Immune responses associated with intestinal nematode infections are characterized by the activation of T-helper 2 (Th2) cells. Previous studies demonstrated that duringTrichinella spiralis infection, Th2 cells contribute to the development of intestinal muscle hypercontractility and to worm eviction from the gut, in part through signal transducer and activator of transcription factor 6 (Stat6). Interleukin-9 (IL-9), a Th2-cellderived cytokine, has pleiotropic activities on various cells that are not mediated through Stat6. In this study, we investigated the role of IL-9 in the generation of enteric muscle hypercontractility in mice infected with the intestinal parasite T. spiralis and the cecal parasite Trichuris muris. Treatment of mice with IL-9 enhanced infection-induced jejunal muscle hypercontractility and accelerated worm expulsion in T. spiralis infection. These effects were associated with an up-regulation of IL-4 and IL-13 production from in vitro-stimulated spleen cells. In addition, increases in the level of intestinal goblet cells and in the level of mouse mucosal mast cell protease 1 (MMCP-1) in serum were observed in infected mice following IL-9 administration. However, the neutralization of IL-9 by anti-IL-9 vaccination or by anti-IL-9 antibody had no significant effect on worm expulsion or muscle contraction in T. spiralis-infected mice. In contrast, the neutralization of IL-9 significantly attenuated T. muris infection-induced colonic muscle hypercontractility and inhibited worm expulsion. The attenuated expulsion of the parasite by IL-9 neutralization was not accompanied by changes in goblet cell hyperplasia or the MMCP-1 level. These findings suggest that IL-9 contributes to intestinal muscle function and to host protective immunity and that its importance and contribution may differ depending on the type of nematode infection.

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“…IFN-␥ appears to play an important role in the progression of sepsis and systemic inflammatory response syndrome through its ability to amplify the proinflammatory response (10,24). The expression of IFN-␥ is regulated by a complex interaction of macrophage-and lymphocyte-derived cytokines and cell surface proteins.…”

Section: Endotoxin (Lipopolysaccharide [Lps]mentioning

confidence: 99%

Cellular Mechanisms That Cause Suppressed Gamma Interferon Secretion in Endotoxin-Tolerant Mice

Varma¹,

Toliver‐Kinsky

Chen³

et al. 2001

Infect Immun

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Endotoxin (lipopolysaccharide [LPS]) tolerance is a state of altered immunity characterized, in part, by suppression of LPS-induced gamma interferon (IFN-γ) expression. However, the cellular mediators regulating LPS-induced production of IFN-γ in normal mice and the effect of LPS tolerance on these mediators has not been well characterized. Our studies show that macrophage dysfunction is the primary factor causing suppressed IFN-γ expression in LPS-tolerant mice. Specifically, LPS-tolerant macrophages have a markedly impaired ability to induce IFN-γ secretion by T cells and NK cells obtained from either control or LPS-tolerant mice. However, T cells and NK cells isolated from LPS-tolerant mice produce normal levels of IFN-γ when cocultured with control macrophages or exogenous IFN-γ-inducing factors. Assessment of important IFN-γ-regulating factors showed that interleukin-12 (IL-12) and costimulatory signals provided by IL-15, IL-18, and CD86 are largely responsible for LPS-induced IFN-γ expression in control mice. IL-10 is an inhibitor of IFN-γ production in both the control and LPS-tolerant groups. Expression of IL-12 and the IL-12 receptor β1 (IL-12Rβ1) and IL-12Rβ2 subunits are suppressed in the spleens of LPS-tolerant mice. LPS-tolerant splenocytes also exhibit decreased production of IL-15 and IL-15Rα. However, expression of IL-18 and the B7 proteins CD80 and CD86 are unchanged or increased compared to controls after induction of LPS tolerance. CD28, a major receptor for B7 proteins, is also increased in the spleens of LPS-tolerant mice. Expression of the inhibitory cytokine IL-10 and the IL-10R are sustained after induction of LPS tolerance. These data show that suppression of IFN-γ production in LPS-tolerant mice is largely due to macrophage dysfunction and provide insight into the cellular alterations that occur in LPS tolerance. This study also better defines the factors that mediate LPS-induced IFN-γ production in normal mice

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IL-9 Protects Mice from Gram-Negative Bacterial Shock: Suppression of TNF-α, IL-12, and IFN-γ, and Induction of IL-10

Cited by 61 publications

References 42 publications

IL-9 Inhibits Oxidative Burst and TNF-α Release in Lipopolysaccharide-Stimulated Human Monocytes Through TGF-β

IL-9 Inhibits Oxidative Burst and TNF-α Release in Lipopolysaccharide-Stimulated Human Monocytes Through TGF-β

Modulation of Intestinal Muscle Contraction by Interleukin-9 (IL-9) or IL-9 Neutralization: Correlation with Worm Expulsion in Murine Nematode Infections

Cellular Mechanisms That Cause Suppressed Gamma Interferon Secretion in Endotoxin-Tolerant Mice

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