Cutting Edge: IL-18-Transgenic Mice: In Vivo Evidence of a Broad Role for IL-18 in Modulating Immune Function

Hoshino, Tomoaki; Kawase, Yusuke; Okamoto, Masaki; Yokota, Koichi; Yoshino, Kohichiro; Yamamura, Ken‐ichi; Miyazaki, Junichi; Young, Howard A.; Ōizumi, Kōtaro

doi:10.4049/jimmunol.166.12.7014

Cited by 124 publications

(89 citation statements)

References 24 publications

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“…Interestingly, IL-18 has also a role in the Th2 immune response since it enhances IL-13 production by T and NK cells when combined with IL-2 [42] and induces the secretion of IL-4, IL-5 and IL-10 in vivo in mouse models of disease [43][44][45]. Consistent with these observations IL-18 transgenic mice have been shown to produce high levels of both Th1 and Th2 cytokines [46]. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10…”

Section: Interleukin-18supporting

confidence: 63%

From IL-15 to IL-33: the never-ending list of new players in inflammation. Is it time to forget the humble aspirin and move ahead?

D’Acquisto

Μaione

Pederzoli-Ribeil

2010

Biochemical Pharmacology

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Section: Interleukin-18supporting

confidence: 63%

From IL-15 to IL-33: the never-ending list of new players in inflammation. Is it time to forget the humble aspirin and move ahead?

D’Acquisto

Μaione

Pederzoli-Ribeil

2010

Biochemical Pharmacology

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“…It has been previously demonstrated that IL-18 induces the production of both Th1-and Th2-type cytokines, including IL-13, -4 and IFN-c, both in vitro and in vivo [16][17][18]. Very recently, the present authors established lung-specific IL-18 Tg mice that constitutively overproduce IL-18 in their lungs.…”

Section: Discussionmentioning

confidence: 94%

“…It has been reported that low levels of pro-and mature IL-18 proteins are expressed in the lungs of healthy subjects [15]. HOSHINO and co-workers [16][17][18] have shown that IL-18 can act as a co-factor for both Th1 and Th2 cell development, and several studies have subsequently reported that IL-18 may be involved in the development of Th2-type-diseases, such as asthma [14]. The present authors have previously demonstrated that treatment with recombinant IL-18 plus IL-2 induces pulmonary inflammation and lung injury in mice [19], and IL-18 and its receptor are strongly expressed in the human lung in idiopathic pulmonary fibrosis [15].…”

mentioning

confidence: 99%

Interleukin-18 production and pulmonary function in COPD

Imaoka

Hoshino

Takei³

et al. 2007

Eur Respir J

122

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Interleukin (IL)-18 production and pulmonary function were evaluated in patients with chronic obstructive pulmonary disease (COPD) in order to determine the role of IL-18 in COPD.Immunohistochemical techniques were used to examine IL-18 production in the lungs of patients with very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV, n516), smokers (n527) and nonsmokers (n523). Serum cytokine levels and pulmonary function were analysed in patients with GOLD stage I-IV COPD (n562), smokers (n534) and nonsmokers (n547).Persistent and severe small airway inflammation was observed in the lungs of ex-smokers with very severe COPD. IL-18 proteins were strongly expressed in alveolar macrophages, CD8+ Tcells, and both the bronchiolar and alveolar epithelia in the lungs of COPD patients. Serum levels of IL-18 in COPD patients and smokers were significantly higher than those in nonsmokers. Moreover, serum levels of IL-18 in patients with GOLD stage III and IV COPD were significantly higher than in smokers and nonsmokers. There was a significant negative correlation between serum IL-18 level and the predicted forced expiratory volume in one second in patients with COPD. In contrast, serum levels of IL-4, IL-13 and interferon-c were not significantly increased in any of the three groups.In conclusion, overproduction of interleukin-18 in the lungs may be involved in the pathogenesis of chronic obstructive pulmonary disease.

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“…Furthermore, when IL-18 was combined with IL-2, there was a synergistic induction of IL-13 in both T and NK cells [17]. IL-18 can also induce IgE, IgG1 and Th2 cytokine production in murine experimental models [19,20], and IL-18 transgenic mice produce higher levels of IL-4, IL-5, IL-13 and IFN-c [21]. Taken together these studies indicate that IL-18 is a pleiotropic cytokine that may under some circumstances augment type 2 as well as type 1 immunity.…”

Section: Introductionmentioning

confidence: 99%

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-c-dominant response associated with susceptibility. However, blocking IFN-c under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4 + T cells and DX5 + TCR -cells were identified as the major producers of IL-13, and the DX5 + TCRcells were phenotyped as NK cells, since they expressed CD11b, IL-2Rb and Ly49C but not c-kit or FceRI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4 + T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 + T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection. IntroductionThe host protective response that develops following infection varies greatly with the particular pathogen. The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1-3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.Typically, type 2 responses leading to resistance require the development of IL-4-producing effector CD4 + T cells, which then utilize autocrine IL-4 for their rapid expansion [3]. These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9]. In the Th2 cell differentiation model just described, blockade of IL-4 production with B7 antagonists would be expected to also inhibit IL-13 production. However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and can differentially regulate these two cytokines. Consistent with these fin...

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Cutting Edge: IL-18-Transgenic Mice: In Vivo Evidence of a Broad Role for IL-18 in Modulating Immune Function

Cited by 124 publications

References 24 publications

From IL-15 to IL-33: the never-ending list of new players in inflammation. Is it time to forget the humble aspirin and move ahead?

From IL-15 to IL-33: the never-ending list of new players in inflammation. Is it time to forget the humble aspirin and move ahead?

Interleukin-18 production and pulmonary function in COPD

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

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