Dataset Information

Progranulin-derived Atsttrin directly binds to TNFRSF25 (DR3) and inhibits TNF-like ligand 1A (TL1A) activity.

ABSTRACT: Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we screened the associations of Atsttrin and other members in TNFR subfamily, which led to the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family. Similar to TNFR1 and TNFR2, DR3 also directly bound to Atsttrin. The first three cysteine-rich domains (CRD) in the extracellular portion of DR3 were required for this interaction. Atsttrin inhibited the interaction between DR3 and its TNF-Like Ligand 1A (TL1A). In addition, Atsttrin inhibited TL1A-stimulated target gene expressions and neutralized TL1A-enhanced osteoclastogenesis in vitro. Furthermore, Atsttrin ameliorated the pathology in dextran sulfate sodium induced colitis. Taken together, these findings not only provide the new insights into Atsttrin's therapeutic action in inflammatory arthritis, but may also present Atsttrin as a novel biological agent for treating various types of diseases associated with TL1A/DR3 pathway.

SUBMITTER: Liu C

PROVIDER: S-EPMC3961393 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Progranulin-derived Atsttrin directly binds to TNFRSF25 (DR3) and inhibits TNF-like ligand 1A (TL1A) activity.

Liu Cui C Li Xing-Xia XX Gao Wei W Liu Wen W Liu De-Shan DS

PloS one 20140320 3

Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we screened the associations of Atsttrin and other members in TNFR subfamily, which led to the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family. Similar to TNFR1 and TNFR2, DR3 also directly bound to Atsttrin. The first three cysteine-rich domains (CRD) in the extracellular port ...[more]

PMID: 24651300

Similar Datasets

Project description:TL1A and its functional receptor DR3 are members of the TNF/TNFR superfamilies of proteins. Binding of APC-derived TL1A to lymphocytic DR3 provides co-stimulatory signals for activated lymphocytes. DR3 signaling affects the proliferative activity of and cytokine production by effector lymphocytes, but also critically influences the development and suppressive function of regulatory T-cells. DR3 was also found to be highly expressed by innate lymphoid cells (ILCS), which respond to stimulation by TL1A. Several recent studies with transgenic and knockout mice as well as neutralizing or agonistic antibodies for these two proteins, have clearly shown that TL1A/DR3 are important mediators of several chronic immunological disorders, including Inflammatory Bowel Disease (IBD). TL1A and DR3 are abundantly localized at inflamed intestinal areas of patients with IBD and mice with experimental ileitis or colitis and actively participate in the immunological pathways that underlie mucosal homeostasis and intestinal inflammation. DR3 signaling has demonstrated a dichotomous role in mucosal immunity. On the one hand, during acute mucosal injury it exerts protective functions by ameliorating the severity of acute inflammatory responses and facilitating tissue repair. On the other hand, it critically participates in the pro-inflammatory pathways that underlie chronic inflammatory responses, such as those that take place in IBD. These effects are mediated through modulation of the relative mucosal abundance and function of Th1, Th2, Th17, Th9, and Treg lymphocytes, but also of all types of ILCs. Recently, an important role was demonstrated for TL1A/DR3 as potential mediators of intestinal fibrosis that is associated with the presence of gut inflammation. These accumulating data have raised the possibility that TL1A/DR3 pathways may represent a valid therapeutic target for chronic immunological diseases. Nevertheless, applicability of such a therapeutic approach will greatly rely on the net result of TL1A/DR3 manipulation on the various cell populations that will be affected by this approach.

Project description:BackgroundTNF-like cytokine 1A (TL1A) is a subgroup of the tumor necrosis factor superfamily that exerts pleiotropic effects on cell proliferation, inflammation, activation, and differentiation of immune cells. The purpose of the current study is to investigate the clinical significance of TL1A expression in coronary and peripheral blood of patients with acute coronary syndrome (ACS) to determine if TL1A levels can serve as an accurate prognostic indicator.MethodsA total of 141 patients undergoing coronary angiography were divided into 4 groups: Control (n = 35), Unstable Angina (UA) (n = 35), acute non-ST segment elevation myocardial infarction (NSTEMI) (n = 37), and acute ST segment elevation myocardial infarction (STEMI) (n = 34). The levels of TL1A, MPO, hs-CRP, and IL-10 were detected in coronary and peripheral blood using enzyme linked immunosorbent assay (ELISA), and the MACE incidence rates were compared during 26.3 months of follow-up.ResultsTL1A levels were not significantly different between the UA group and control group. In the UA group, TL1A levels were not significantly different between coronary blood and peripheral blood. However, TL1A levels were higher in the STEMI and NSTEMI groups than in the control group (P < .05). Moreover, TL1A levels in the coronary blood of the STEMI and NSTEMI groups were higher than in the peripheral blood (P < .05). The expression of TL1A in the coronary blood was the highest in the STEMI group. In addition, TL1A level in the coronary blood was highly correlated with levels in the peripheral blood (correlation coefficient: 0.899, P < .001). The hs-CRP and MPO levels in the coronary and peripheral blood of all the UA, NSTEMI, and STEMI groups were higher than the control group. Plasma IL-10 levels in all the UA, NSTEMI and STEMI groups were lower than those in the control group. Plasma TL1A level was positively correlated with the cTnI level, degree of coronary thrombus burden, occurrence of slow coronary flow / no coronary reflow and MACE, but negatively correlated with the IL-10 level or non-correlated with the Syntax score.ConclusionPlasma TL1A concentration levels can be used as a predictor of inflammatory response and prognosis in patients with ACS.Trial registrationClinicalTrials.gov, number: NCT02430025; Unique Protocol ID: FJPH20150101; Brief Title: Fujian Province Cardiovascular Diseases Study (FJCVD).

Dataset Information

Progranulin-derived Atsttrin directly binds to TNFRSF25 (DR3) and inhibits TNF-like ligand 1A (TL1A) activity.

Publications

Progranulin-derived Atsttrin directly binds to TNFRSF25 (DR3) and inhibits TNF-like ligand 1A (TL1A) activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets