Interleukin-33 – cytokine of dual function or novel alarmin?

Haraldsen, Guttorm; Balogh, Johanna; Pollheimer, Jürgen; Sponheim, Jon; Küchler, Axel M.

doi:10.1016/j.it.2009.03.003

Cited by 277 publications

(236 citation statements)

References 86 publications

(117 reference statements)

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“…Belonging to this family, IL33 is a bona fide alarmin mediating "danger" signals that activate the innate immune responses (39). Indeed, epithelial cell-derived IL33 and its receptor are deregulated in human IBD patients and in mouse models of colon inflammation (40,41). Here, the relevance of IL33 is further proved by data showing that exogenous IL33 administration is pathogenic during the acute phase of DSS-induced inflammation (42) or that IL33 KO mice are less susceptible to DSSinduced colitis because of reduced granulocytes infiltration (43).…”

Section: Discussionmentioning

confidence: 99%

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

et al. 2015

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Mast cells (MC) are immune cells located next to the intestinal epithelium with regulatory function in maintaining the homeostasis of the mucosal barrier. We have investigated MC activities in colon inflammation and cancer in mice either wildtype (WT) or MC-deficient (Kit W-sh ) reconstituted or not with bone marrow-derived MCs. Colitis was chemically induced with dextran sodium sulfate (DSS). Tumors were induced by administering azoxymethane (AOM) intraperitoneally before DSS. Following DSS withdrawal, Kit W-sh mice showed reduced weight gain and impaired tissue repair compared with their WT littermates or Kit W-sh mice reconstituted with bone marrowderived MCs. MCs were localized in areas of mucosal healing rather than damaged areas where they degraded IL33, an alarmin released by epithelial cells during tissue damage. Kit W-sh mice reconstituted with MC deficient for mouse mast cell protease 4 did not restore normal mucosal healing or reduce efficiently inflammation after DSS withdrawal. In contrast with MCs recruited during inflammation-associated wound healing, MCs adjacent to transformed epithelial cells acquired a protumorigenic profile. In AOM-and DSS-treated WT mice, high MC density correlated with high-grade carcinomas. In similarly treated Kit W-sh mice, tumors were less extended and displayed lower histologic grade. Our results indicate that the interaction of MCs with epithelial cells is dependent on the inflammatory stage, and on the activation of the tissue repair program. Selective targeting of MCs for prevention or treatment of inflammation-associated colon cancer should be timely pondered to allow tissue repair at premalignant stages or to reduce aggressiveness at the tumor stage. Cancer Res; 75(18); 3760-70. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

et al. 2015

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“…Subsequently, IL-33 has been identified in the nucleus of epithelial cells [21], synovial fibroblasts [22], and monocytes [30]. Finally, it has been recently suggested that IL-33 might function as an "alarmin", being secreted during cell necrosis, to initiate immune responses [21,31].…”

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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“…Like other IL-1 family members, IL-33 can be cleaved by caspase-1, although it appears that this cleavage leads to functional inactivation (11), leading to speculation that IL-33 primarily functions as a chromatin-associated nuclear factor (12). However, bioactive IL-33 can be generated following pro-IL-33 cleavage by other proteases such as neutrophil elastase and cathepsins, suggesting that bioactive IL-33 may be released into the extracellular environment (13).…”

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confidence: 99%

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

Hung

Lewkowich

Dawson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

187

174

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Parasitic helminths are a major cause of chronic human disease, affecting more than 3 billion people worldwide. Host protection against most parasitic helminths relies upon Type 2 cytokine production, but the mechanisms that regulate interleukin (IL) 4 and 13 production from CD4 + T helper 2 cells (T H 2) and innate lymphoid type 2 cells (ILC2s) remain incompletely understood. The epithelial cell-derived cytokines IL-25 and IL-33 promote Type 2 responses, but the extent of functional redundancy between these cytokines is unclear and whether Type 2 memory relies upon either IL-25 or IL-33 is unknown. Herein, we demonstrate a pivotal role for IL-33 in driving primary and anamnestic immunity against the rodent hookworm Nippostrongylus brasiliensis. IL-33-deficient mice have a selective defect in ILC2-derived IL-13 during both primary and secondary challenge infections but generate stronger canonical CD4 + T helper 2 cells responses (IL-4, IgE, mast cells, and basophils) than WT controls. Lack of IL-13 production in IL-33-deficient mice impairs resistin-like molecule beta (RELMβ) expression and eosinophil recruitment, which are two mechanisms that eliminate N. brasiliensis parasites from infected hosts. Thus, IL-33 is requisite for IL-13 but not IL-4-driven Type 2 responses during hookworm infection. mucosal immunity | gastrointestinal nematode | inflammation

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Interleukin-33 – cytokine of dual function or novel alarmin?

Cited by 277 publications

References 86 publications

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

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

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

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