Suppression of Interleukin-33 Bioactivity through Proteolysis by Apoptotic Caspases

Lüthi, Alexander U.; Cullen, Sean P.; McNeela, Edel A.; Duriez, Patrick J.; Afonina, Inna S.; Sheridan, Clare; Brumatti, Gabriela; Taylor, Rebecca C.; Kersse, Kristof; Vandenabeele, Peter; Lavelle, Ed C.; Martin, Séamus J.

doi:10.1016/j.immuni.2009.05.007

Cited by 618 publications

(576 citation statements)

References 25 publications

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…IL‐33 can be produced by endothelial cells, epithelial cells and fibroblasts. IL‐33 intracellularly regulates gene expression,114, 115 and is also an alarm mediator when released from injured cells 116, 117, 118…”

Section: Roles Of Inflammatory Cytokines In Sci Repairmentioning

confidence: 99%

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

et al. 2018

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The balance of inflammation is critical to the repair of spinal cord injury (SCI), which is one of the most devastating traumas in human beings. Inflammatory cytokines, the direct mediators of local inflammation, have differential influences on the repair of the injured spinal cord. Some inflammatory cytokines are demonstrated beneficial to spinal cord repair in SCI models, while some detrimental. Various animal researches have revealed that local delivery of therapeutic agents efficiently regulates inflammatory cytokines and promotes repair from SCI. Quite a few clinical studies have also shown the promotion of repair from SCI through regulation of inflammatory cytokines. However, local delivery of a single agent affects only a part of the inflammatory cytokines that need to be regulated. Meanwhile, different individuals have differential profiles of inflammatory cytokines. Therefore, future studies may aim to develop personalized strategies of locally delivered therapeutic agent cocktails for effective and precise regulation of inflammation, and substantial functional recovery from SCI.

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“…1,10 However, as with the IL-1 family members IL-1b and IL-18, IL-33 lacks a classical signal sequence necessary for secretion via the endoplasmic reticulum/Golgi pathway. 2,11,33,42,43 Active caspase-1 has been confirmed to be a regulator of the unconventional secretion of such proteins. 47 IL-1b and IL-18 are well known to be synthesized as a biologically inactive 33-kDa pro-IL-1b and 23-kDa pro-IL-18 which reside in the cytosolic compartment and to be subsequently cleaved by caspase-1 to secrete the active 17-kDa IL-1b and 18-kDa IL-18.…”

Section: Can Il-33 Be Secreted?mentioning

confidence: 99%

“…2,[39][40][41][42][43][44][45][46] The hydrolyzing role of caspase-1 in the full-length IL-33 is also brought into question by recent findings. [42][43][44][45][46] For novel insights into the biological functions of the IL-33/ST2 pathway, it is crucial to address such questions and identify possible mechanisms underlying these discrepancies. This mini review summarizes the recent progress in our understanding of how IL-33 displays a potential immunoregulatory role with a particular focus on the mechanisms relating to its processing and secretion.…”

Section: Introductionmentioning

confidence: 99%

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The enigmatic processing and secretion of interleukin-33

Zhao

2010

Cell Mol Immunol

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Interleukin-33 (IL-33) is the most attractive novel cytokine identified as an IL-1 family member. IL-33 was first named NF-HEV (nuclear factor from high endothelial venules), as it was known to interact with nuclear chromatin although its exact intracellular functions are still to be clarified. IL-33 is now recognized as the specific ligand for the orphan IL-1 receptor family member ST2 and to be involved in polarization of T cells towards T helper 2 cell phenotype and in activation of mast cells, bosophils, eosinophils and natural killer cells. It is essential for IL-33 to be extracellularly released in order to bind to the ST2 receptor and consequently play a crucial role in inflammatory, infectious and autoimmune diseases. However, like the IL-1 family members, IL-1b and IL-18, IL-33 mRNA is translated without a signal sequence for secretion. Additionally, IL-33 cannot be released by the processing and secretion mechanism shared by IL-1b and IL-18 as IL-33 is not a substrate of caspase-1 and does not require proteolysis for activation. In contrast, IL-33 can be inactivated by apoptotic caspases. Accordingly, IL-33 is proposed to be released as an alarmin from necrotic cells but to be deleted during apoptosis. Besides the known autocrine, paracrine, intracrine, juxtacrine and retrocrine mechanisms of cellular interaction with cytokines, release by necrotic cells is another pathway for a cytokine to display its function, which we suggest might be called 'necrocrine'. This mini review summarizes recent progress of how IL-33 displays potential immunoregulatory roles with a particular focus on its enigmatic production. INTRODUCTIONIn the ever-growing list of cytokines, interleukin-33 (IL-33), one of the IL-1 family members (also called IL-1F11), is a most interesting novel cytokine. This cytokine was first named in 2003 as NF-HEV (nuclear factor from high endothelial venules), as it was known to interact with nuclear chromatin in an intracrine manner. 1 It was rediscovered in 2005 as the specific extracellular ligand for the orphan IL-1 receptor family member ST2, and named IL-33. 2 ST2 (also known as IL-1RL1, DER4, T1 and FIT-1) belongs to the Toll-like/IL-1 receptor superfamily. [3][4][5] It has been well documented to be the cellular marker for differentiated T helper 2 (Th2) cells 6,7 and to be expressed on mast cells. 8,9 As a nuclear factor, the intracellular functions of IL-33 remain to be further clarified, although overexpression studies suggested a role as a transcriptional repressor. 10 As an extracellular cytokine, binding of IL-33 to the ST2 receptor activates nuclear factor-kB and mitogen-activated protein kinases, [3][4][5]11 and is involved in the polarization of T cells towards the Th2 cell phenotype 2,6,7,[11][12][13][14] and in activation of mast cells, 15-20 bosophils, 14,20-24 eosinophils, 24-26 and natural killer cells. 14,27 IL-33 must be present extracellularly in order to play the crucial role in inflammatory, infectious and autoimmune diseases including anaphylactic shock, asthma, rheum...

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Suppression of Interleukin-33 Bioactivity through Proteolysis by Apoptotic Caspases

Cited by 618 publications

References 25 publications

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

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

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

The enigmatic processing and secretion of interleukin-33

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