IL-18 induction of IgE: dependence on CD4+ T cells, IL-4 and STAT6

Yoshimoto, Tomohiro; Mizutani, Hitoshi; Tsutsui, Hiroko; Noben-Trauth, Nancy; Yamanaka, Keiichi; Tanaka, Minoru; Izumi, Shinzo; Okamura, Haruki; Paul, William E.; Nakanishi, Kenji

doi:10.1038/77811

Cited by 320 publications

(298 citation statements)

References 34 publications

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“…However, our results indicate that this is unlikely, because the absence of IL-12 did not decrease either IL-13 production by MLN cells or IL-13-dependent worm expulsion. Previous studies also suggested that IL-18 could induce IL-4 and associated IgE and IgG1 production in vivo [19,20]. In the IL-4-dominant response to T. muris, IL-18 has further been shown to down-regulate IL-13 production [13].…”

Section: Discussionmentioning

confidence: 95%

“…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%

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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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Section: Discussionmentioning

confidence: 95%

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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“…While IL-18 clearly enhances Th1 responses, it is less clear whether IL-18 is capable of initiating Th1 differentiation in the absence of IL-12 6 7 8 9 10. Although a majority of published reports link IL-18 with Th1-associated functions, IL-18 has recently been shown to augment Th2 responses 11 12 13 14. Administration of IL-18 to mice led to an increase in IL-4 production and elevated serum IgE.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Interleukin (Il)-18 Receptor α Chain Expression on Cd4+ T Cells during T Helper (Th)1/Th2 Differentiation

Smeltz

Chen

Hu‐Li

et al. 2001

The Journal of Experimental Medicine

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Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12–mediated interferon (IFN)-γ production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor α chain (IL-18Rα) expression. The majority of peripheral CD4+ T cells constitutively expressed the IL-18Rα. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18Rα expression was observed. IL-12–mediated upregulation of IL-18Rα required IFN-γ. Activated CD4+ T cells that expressed low levels of IL-18Rα could produce IFN-γ when stimulated with the combination of IL-12 and IL-18, while CD4+ cells which expressed high levels of IL-18Rα could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Rα expression. Both IL-4−/− and signal transducer and activator of transcription (Stat)6−/− T cells expressed higher levels of IL-18Rα after TCR stimulation. Furthermore, activated T cells from Stat6−/− mice produced more IFN-γ in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18Rα by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.

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“…IL-18, in turn, helps induce the IL-12 high affinity receptor, establishing a feed-forward Th1-amplifying loop [11,17]. Surprisingly, in the absence of a Th1-polarizing environment, IL-18 can promote the differentiation of Th2 cells, a CD4 + T cell subset dominating allergic responses and characterized by the expression of IL-4 and IL-13 [11, 17,18].…”

Section: Main Effects Of Il-1b and Il-18 On T Helper Cell Polarizationmentioning

confidence: 99%