Shenkangling plays a role of Yishenhuoxue effect for the treatment of children with nephrotic syndrome. The aim of this study was to investigate the effects of Shenkangling intervention on the mitogen-activated protein kinase (MAPK) pathway in rats with Adriamycin-induced nephropathy (AN) and its underlying mechanism of action. Nephrosis was induced in healthy Sprague-Dawley rats by doxorubicin...

Tight control of T-cell proliferation and effector function is essential to ensure an effective but appropriate immune response. Here, we reveal that this is controlled by the metalloprotease-mediated cleavage of LAG-3, a negative regulatory protein expressed by all activated T cells. We show that LAG-3 cleavage is mediated by two transmembrane metalloproteases, ADAM10 and ADAM17, with the acti...

TNF, a potent proinflammatory cytokine, is synthesized as a membrane-anchored precursor and proteolytically released from cells. Soluble TNF is the primary mediator of pathologies such as rheumatoid arthritis, Crohn’s disease, and endotoxin shock. The TNFconverting enzyme (TACE), a disintegrin and metalloprotease 17 (ADAM17), has emerged as the best candidate TNF sheddase, but other proteinases...

iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-α convertase (TACE), which controls shedding of TNF-α and its biological activity in vivo. TACE is a potential target to treat TNF-α-dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. ...

Activation of the TPL2-MKK1/2-ERK1/2 signalling pathway is essential for lipopolysaccharide (LPS)-stimulated production of TNF alpha in macrophages. Here, we demonstrate that, unexpectedly, TPL2-deficient or MKK1-inhibited macrophages produce near normal levels of pre-TNF alpha when TLR2, TLR4 and TLR6 are activated by their respective agonists, but fail to secrete TNFalpha. We show that LPS st...

Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and t...

TNFα-converting enzyme (TACE/ADAM17) is a membrane-bound proteolytic enzyme with a diverse set of target molecules. Most importantly, TACE is indispensable for the release and activation of pro-TNFα and the ligands for epidermal growth factor receptor in vivo. Previous studies suggested that the overproduction of TACE is causally related to the pathogenesis of inflammatory diseases and cancers....

PURPOSE The graft versus leukemia effect by natural killer (NK) cells prevents relapse following hematopoietic stem cell transplantation. We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. EXPERIMENTAL DESIGN We investigated the ability of our fu...

Proteolytic shedding of cell surface proteins generates paracrine signals involved in numerous signaling pathways. Neuregulin 1 (NRG1) type III is involved in myelination of the peripheral nervous system, for which it requires proteolytic activation by proteases of the ADAM family and BACE1. These proteases are major therapeutic targets for the prevention of Alzheimer's disease because they are...

The immunoreceptor NKG2D promotes immunosurveillance of malignant cells and protects the host from tumor initiation by activating natural killer cells and costimulating CD8 T cells. NKG2D-mediated recognition of malignant cells by cytotoxic lymphocytes is enabled through the tumor-associated expression of NKG2D ligands (NKG2DL) resulting from cellular or genotoxic stress. Shedding of NKG2DL is ...