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...