Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33

Pecaric‐Petkovic, Tatjana; Didichenko, Svetlana A.; Kaempfer, Sacha; Spiegl, Nicole; Dahinden, Clemens A.

doi:10.1182/blood-2008-05-157818

Cited by 385 publications

(386 citation statements)

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“…J. Immunol. 2011 well documented [20,25]. Recently, it was shown that the resolution of allergic inflammation and airway hyperresponsiveness depend on the disruption of ST2/IL-33 pathway [8] and that IL-33-neutralizing antibody administration inhibits airway inflammation in mice [37].…”

Section: Discussionmentioning

confidence: 99%

“…IL-33 signals through a heterodimeric membrane receptor composed of ST2 and the IL-1R1 accessory protein and activates basophils [20,21], mast cells [22,23], eosinophils [24,25], NK and NKT cells [26], Th2 lymphocytes [5,27] and macrophages [14]. In accordance with its Th2 functions, administration of IL-33 into naive mice induces severe inflammation in the lung and digestive tract with elevated levels of IL-4, IL-5 and IL-13, splenomegaly and increased serum Ig [10].…”

Section: Introductionmentioning

confidence: 99%

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IL‐33‐activated dendritic cells are critical for allergic airway inflammation

et al. 2011

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IL-33, a new member of the IL-1 family cytokine, is involved in Th2-type responses in a wide range of diseases and signals through the ST2 receptor expressed on many immune cells. Since the effects of IL-33 on DCs remain controversial, we investigated the ability of IL-33 to modulate DC functions in vitro and in vivo. Here, we report that IL-33 activates myeloid DCs to produce IL-6, IL-1b, TNF, CCL17 and to express high levels of CD40, CD80 OX40L and CCR7. Importantly, IL-33-activated DCs prime naive lymphocytes to produce the Th2 cytokines IL-5 and IL-13, but not IL-4. In vivo, IL-33 exposure induces DC recruitment and activation in the lung. Using an OVA-induced allergic lung inflammation model, we demonstrate that the reduced airway inflammation in ST2-deficient mice correlates with the failure in DC activation and migration to the draining LN. Finally, we show that adoptive transfer of IL-33-activated DCs exacerbates lung inflammation in a DC-driven model of allergic airway inflammation. These data demonstrate for the first time that IL-33 activates DCs during antigen presentation and thereby drives a Th2-type response in allergic lung inflammation. IntroductionAllergic asthma is a chronic disorder characterized by eosinophilic airway inflammation, mucus hypersecretion, antigenspecific-IgE antibodies, airway remodeling and increased airway hyperreactivity [1,2]. The process of airway inflammation involves various cells types, such as eosinophils, mast cells, epithelial cells, lymphocytes and DCs. Th2 cells have been shown to play a predominant role in allergic asthma and Th2 cytokines, such as IL-4, IL-5 and IL-13, exacerbate disease severity [3,4]. IL-33, the recently discovered Th2 cytokine, is found at high levels in the plasma of asthmatic patients [5,6] and in the lungs of mice during experimental allergic asthma [7,8].IL-33 is a member of IL-1 family [9][10][11]. Like IL-1b or IL-18, IL-33 is synthesized as a precursor and can be cleaved by caspase-1 and 3 but the cleavage products are biologically less active than the precursor [12,13]. In contrast to the other IL-1 family members, IL-33 is mainly expressed in non-hematopoietic cells such as fibroblasts, epithelial cells and endothelial cells [10,14,15]. Because of its nuclear localization sequence, IL-33 is usually present in the nucleus, where it acts as a potential transcriptional repressor [16]. Recently, IL-33 has been shown to be released from necrotic cells and may act as an alarmin in a similar manner to IL-1a [17] or high mobility group box1 protein HMGB1 [18,19]. [14]. In accordance with its Th2 functions, administration of IL-33 into naive mice induces severe inflammation in the lung and digestive tract with elevated levels of IL-4, IL-5 and IL-13, splenomegaly and increased serum Ig [10]. In vitro, IL-33 has also been reported to polarize naive CD4 1 T cells to produce IL-5 and IL-13, but not . Polarization of this atypical Th2 population is independent of IL-4, STAT6 and GATA3. On macrophages, IL-33 amplifies IL-13-mediated polarization...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

et al. 2011

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“…1,2,8 In addition to the evidence of enhanced NF-kB activity in peripheral blood mononuclear cells of asthmatic patients, 9 our previous studies also demonstrated that NF-kB signal transduction, p38 MAPK and extracellular signal-regulated kinase (ERK) pathways played pivotal roles in regulating IL-3, IL-5 and granulocyte macrophage colonystimulating factor-induced intercellular adhesion molecule (ICAM)-1 expression and Th17 cytokine-elicited cytokine production from human eosinophils. 10,11 In an attempt to further investigate the activation of eosinophils induced by IL-33, we elucidated the intracellular signaling mechanisms regulating the survival, adhesion, and cytokine and chemokine release from eosinophils activated by IL-33, and we compared the effects of two other structurally and functionally related IL-1 family cytokines, IL-1b and IL-18.…”

Section: Introductionmentioning

confidence: 97%

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

et al. 2009

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The novel interleukin (IL)-1 family cytokine IL-33 has been shown to activate T helper 2 (Th2) lymphocytes, mast cells and basophils to produce an array of proinflammatory cytokines, as well as to mediate blood eosinophilia, IgE secretion and hypertrophy of airway epithelium in mice. In the present study, we characterized the activation of human eosinophils by IL-33, and investigated the underlying intracellular signaling mechanisms. IL-33 markedly enhanced eosinophil survival and upregulated cell surface expression of the adhesion molecule intercellular adhesion molecule (ICAM)-1 on eosinophils, but it suppressed that of ICAM-3 and L-selectin. In addition, IL-33 mediates significant release of the proinflammatory cytokine IL-6 and the chemokines CXCL8 and CCL2. We found that IL-33-mediated enhancement of survival, induction of adhesion molecules, and release of cytokines and chemokines were differentially regulated by activation of the nuclear factor (NF)-kB, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathways. Furthermore, we compared the above IL-33 activities with two structurally and functionally related cytokines, IL-1b and IL-18. IL-1b, but not IL-18, markedly upregulated cell surface expression of ICAM-1. IL-1b and IL-18 also significantly enhanced eosinophil survival, and induced the release of IL-6 and chemokines CXCL8 and CCL2 via the activation of the NF-kB, p38 MAPK and ERK pathways. Synergistic effects on the release of IL-6 were also observed in combined treatment with IL-1b, IL-18 and IL-33. Taken together, our findings provide insight into IL-33-mediated activation of eosinophils via differential intracellular signaling cascades in the immunopathogenesis of allergic inflammation.

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“…IL-33 appears to be predominantly expressed in vivo in endothelial and epithelial cells [20,21], but IL-33 expression may be induced by inflammatory signals in other cell types [11,22]. Cell targets of IL-33 include polarized Th2 cells [11,23,24], mast cells [15,25], basophils [24,26], and dendritic cells [27,28]. Besides these ST2-receptor mediated effects, IL-33 is able to translocate into the nucleus, where it may display transcriptional functions.…”

Section: Introductionmentioning

confidence: 99%

IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

et al. 2011

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1 IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodelingsuggested that expression of IL-33, in contrast to that of IL-1β, is not repressed by PPARγ, likely explaining why IL-33, but not IL-1β, is expressed in adipocytes. The IL-33 receptor ST2L is not constitutively expressed in human bone marrow stromal cells, osteoblasts or CD14-positive monocytes, and IL-33 has no effect on these cells. In addition, although ST2L mRNA is induced by TNF-α and IL-1β in bone marrow stromal cells, IL-33 has the same effects as TNF-α and IL-1β, and, therefore, the biological activity of IL-33 may be redundant in this system. In agreement with this hypothesis, MC3T3-E1 osteoblast-like cells constitutively express ST2L mRNA, and in these cells IL-33 and TNF-α/IL-1β similarly decrease osteocalcin RNA levels in these cells. In conclusion, our results suggest that IL-33 has no direct effects on normal bone remodeling.

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Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33

Cited by 385 publications

References 61 publications

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

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