Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin 33 (IL-33) binds to membrane-bound ST2 (ST2L) and has antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits, and is a prognostic biomarker in patients with cardiovascular diseases. Here we report that a highly local intramyocardial IL-33/ST2 conversation regulates the heart's response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response.H ypertension is the most common cardiovascular risk factor and contributes to widespread morbidity and mortality worldwide (1), but the pathological and molecular mechanisms by which elevated blood pressure promotes vascular disease remain uncertain. Inflammation has been hypothesized to play a role in hypertension as well as the progression of vascular disease (2, 3). Although the association between hypertension and inflammation has now been clearly demonstrated, molecular mechanisms that link hypertension to systemic inflammation are unclear.The soluble receptor ST2 is a prognostic biomarker in patients with cardiovascular disease (4, 5), and serum ST2 levels also predict changes in blood pressure in the community (6). ST2, also known as IL1RL1 (IL-1 receptor like 1), is a member of the IL-1 receptor family, which plays a major role in immune and inflammatory responses (7). At least two forms of ST2 are known, including the transmembrane receptor (ST2L) and the soluble form (sST2) that circulates in blood (8). Membrane-bound ST2L interacts with IL-33, an IL-1 family ligand (9), and IL-33 can have antihypertrophic and antifibrotic effects in the myocardium (10). In contrast, sST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits (10-12). IL-33 is also expressed in endothelial cells (ECs) (13-16), in which it induces angiogenesis (17), expression of adhesion molecules, and inflammatory activation (18). Here we report the surprising finding that endothelial IL-33 from pressure overload induces a selective systemic response, potentially linking hypertension with circulating factors that can affect the vasculature and other organs. Results ST2 Deficiency Exacerbates Pressure Overload-Induced CardiacHypertrophy. Communication between cardiomyocytes, fibroblasts, and ECs is important for normal cardiac function as well as pathophysiology (19,20). We explored intercellular communication in...

IL-20 promotes osteoclast differentiation by inducing RANK and RANKL expression in osteoclast precursors and osteoblasts, respectively.

Stroke is the second leading cause of death and the leading cause of adult disability worldwide. Although different mechanisms are involved in the pathogenesis of stroke, increasing evidence shows that ischemic injury and inflammation account for its pathogenic progression (1, 2). Ischemic brain injury after stroke is a dynamic process that evolves over a period of hours to several days, particularly in the area surrounding the core of the infarct known as the penumbra (3). This process includes oxidative stress, cell death, and inflammation, as well as the activation of endogenous adaptive and regenerative mechanisms. The regulation of many of these processes occurs at the transcriptional level and involves the concerted activation of various transcription factors, including hypoxia-inducible factor 1␣ (HIF-1␣) 2 (4). Ischemic brain injury is a consequence of a severe reduction in the blood supply to the affected region. The deficits can often be permanent because adult neurons fail to regenerate. After they have been activated by injury, astrocytes and microglia release factors that recruit other astrocytes and microglia to the injury site. This process can lead to glial scar formation, which has the potential to block the growth and maturation of neural progenitors and to impede neovascularization, thus inhibiting recovery after injury (5).Cytokines are up-regulated in the brain in a variety of diseases, including stroke, and are expressed not only in the cells of the immune system, but are also produced by resident brain cells, including glia cells and neurons (6 -8). Chemokine expression precedes inflammatory cell infiltration following cerebral ischemia (9). IL-1␤ (10, 11), TNF-␣ (12, 13), , and MCP-1 (15) appear to exacerbate cerebral injury; however, TGF-␤ (16) and IL-10 (17) may be neuroprotective.The pleiotropic inflammatory cytokine IL-20, a member of IL-10 family which includes IL-10, IL-19, IL-20, IL-22, 19), is expressed in monocytes, epithelial cells, and endothelial cells and exerts its biological functions on multiple cell types by activating IL-20R1/IL-20R2 or IL-22R1/ . IL-20 is involved in various inflammatory diseases (21), such as psoriasis (18,22,23), rheumatoid arthritis (24), atherosclerosis (25,26), and renal failure (27). Recently, IL-20 has been reported to regulate angiogenesis (28,29). It is also an arteriogenic cytokine based on its actions in remodeling collateral networks and improving the functions of ischemic hind limbs (30).Our previous study showed that hypoxia induced IL-20 in endothelial cells (26). Little is known about the molecular mechanism of gene regulation of IL-20 in hypoxia and its clinical implications. In the present study, we found up-regulation of IL-20 under hypoxic conditions in vitro and in the ischemic brain in vivo. We identified IL-20 promoter regions and the functional response elements of the il20 gene in response to hypoxia. We also demonstrated a pathogenic role of IL-20 in ischemic brain injury in vivo using an animal model of transient middle cerebr...

Background: Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, IL-33 is elevated and promotes immune cell activation, leading to the development of asthma. However, which immune cells are responsible for triggering airway hyperreactivity (AHR), inflammation and eosinophilia remained to be clarified. We aimed to elucidate the individual roles of IL-33-activated innate immune cells, including ILC2s and ST2 + myeloid cells, in RSV infection-triggered pathophysiology. Methods:The role of IL-33/ILC2 axis in RSV-induced AHR inflammation and eosinophilia were evaluated in the IL-33-deficient and YetCre-13 Rosa-DTA mice. Myeloidspecific, IL-33-deficient or ST2-deficient mice were employed to examine the role of IL-33 and ST2 signaling in myeloid cells. Results:We found that IL-33-activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2-derived IL-13 was sufficient for RSV-driven AHR, since reconstitution of wild-type ILC2 rescued RSV-driven AHR in IL-13-deficient mice. Meanwhile, myeloid cell-derived IL-33 was required for airway inflammation, ST2 + myeloid cells contributed to exacerbation of airway inflammation, suggesting the importance of IL-33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL-33 signaling. Conclusions:This study highlights the importance of IL-33-activated ILC2s in mediating RSV-triggered AHR and eosinophilia. In addition, IL-33 signaling in myeloid cells is crucial for airway inflammation. K E Y W O R D S asthma, eosinophilia, IL-33, ILC2, respiratory syncytial virus | 819 WU et al.

IL-20 induces proinflammatory, chemotaxtic, and matrix degradative responses in IVD cells especially in combination with IL-1beta. Our study suggests that IL-20 plays an important role in the pathogenesis of disc herniation.

Renal diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), have a great impact on health care systems worldwide. Similar to cardiovascular diseases, renal diseases are inflammatory diseases involving a variety of cytokines. Primary causes of renal injury include ischemia, uremic toxins, bacteremia, or nephrotoxicity. Inflammation represents an important component following kidney injury. Interleukin (IL)-33 is a member of the IL-1 cytokine family, which is widely expressed in epithelial barrier tissues and endothelial cells, and mediates both tissue inflammation and repair responses. IL-33 is released as a nuclear alarmin in response to tissue damage and triggers innate and adaptive immune responses by binding to its receptor, suppression of tumorigenicity 2 (ST2). Recent evidence from clinical and experimental animal studies indicates that the IL-33/ST2 axis is involved in the pathogenesis of CKD, renal graft injury, systemic lupus nephritis, and AKI. In this review, we discuss the pathological and tissue reparative roles of the IL-33/ST2 pathway in different types of renal diseases.

IL-19 expression in uraemic patients correlated with Th2 immune responses which might be involved in the cytokine dysregulation in uraemia.

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.