Epithelial RNase H2 Maintains Genome Integrity and Prevents Intestinal Tumorigenesis in Mice.

Background & Aims: RNase H2 is a holoenzyme, composed of 3 subunits (ribonuclease H2 subunits A, B, and C), that cleaves RNA:DNA hybrids and removes mis-incorporated ribonucleotides from genomic DNA through ribonucleotide excision repair. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and produces the most frequent type of naturally occurring DNA lesion. We investigated whether intestinal epithelial proliferation requires RNase H2 function and whether RNase H2 activity is disrupted during intestinal carcinogenesis.

Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy.

Hypomorphic mutations in the DNA repair enzyme RNase H2 cause the neuroinflammatory autoimmune disorder Aicardi-Goutières syndrome (AGS). Endogenous nucleic acids are believed to accumulate in patient cells and instigate pathogenic type I interferon expression. However, the underlying nucleic acid species amassing in the absence of RNase H2 has not been established yet.

Adam17 Deficiency Promotes Atherosclerosis by Enhanced TNFR2 Signaling in Mice.

Objective: ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in the pathogenesis of this frequent disease.

Approach And Results: Because Adam17-knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice (Adam17), which have low residual Adam17 expression.

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma.

Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth.

Circulating Soluble IL-6R but Not ADAM17 Activation Drives Mononuclear Cell Migration in Tissue Inflammation.

Neutrophil and mononuclear cell infiltration during inflammatory processes is highly regulated. The first cells at the site of infection or inflammation are neutrophils, followed by mononuclear cells. IL-6 plays an important role during inflammatory states.

ADAM17 substrate release in proximal tubule drives kidney fibrosis.

Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors.

Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts.

Rankl, the major pro-osteoclastogenic cytokine, is synthesized as a transmembrane protein that can be cleaved by specific endopeptidases to release a soluble form (sRankl). We have previously reported that interleukin-33 (IL-33) induces expression of Tnfsf11, the Rankl-encoding gene, in primary osteoblasts, but we failed to detect sRankl in the medium. Since we also found that PTH treatment caused sRankl release in a similar experimental setting, we directly compared the influence of the two molecules.

Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics.

Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor of metalloproteinase 3) accumulation in the vascular extracellular matrix in CADASIL is a key contributor to cerebrovascular dysfunction.

Different Soluble Forms of the Interleukin-6 Family Signal Transducer gp130 Fine-tune the Blockade of Interleukin-6 Trans-signaling.

Soluble forms of the IL-6 receptor (sIL-6R) bind to the cytokine IL-6 with similar affinity as the membrane-bound IL-6R. IL-6·sIL-6R complexes initiate IL-6 trans-signaling via activation of the ubiquitously expressed membrane-bound β-receptor glycoprotein 130 (gp130). Inhibition of IL-6 trans-signaling has been shown to be favorable in numerous inflammatory diseases.

ADAM17 controls IL-6 signaling by cleavage of the murine IL-6Rα from the cell surface of leukocytes during inflammatory responses.

The cytokine IL-6 is part of a regulatory signaling network that controls immune responses. IL-6 binds either to the membrane-bound IL-6 receptor-α (classic signaling) or to the soluble IL-6 receptor-α (trans-signaling) to initiate signal transduction via gp130 activation. Because classic and trans-signaling of IL-6 fulfill different tasks during immune responses, controlled shedding of the membrane-bound IL-6 receptor-α from the surface of immune cells can be considered a central regulator of IL-6 function.

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles.

Generation of the soluble interleukin-6 receptor (sIL-6R) is a prerequisite for pathogenic IL-6 trans-signaling, which constitutes a distinct signaling pathway of the pleiotropic cytokine interleukin-6 (IL-6). Although in vitro experiments using ectopically overexpressed IL-6R and candidate proteases revealed major roles for the metalloproteinases ADAM10 and ADAM17 in IL-6R shedding, the identity of the protease(s) cleaving IL-6R in more physiological settings, or even in vivo, remains unknown. By taking advantage of specific pharmacological inhibitors and primary cells from ADAM-deficient mice we established that endogenous IL-6R of both human and murine origin is shed by ADAM17 in an induced manner, whereas constitutive release of endogenous IL-6R is largely mediated by ADAM10.

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit.

ADAM10 and ADAM17 have opposite roles during sprouting angiogenesis.

During angiogenesis, endothelial tip cells start sprouting and express delta-like 4 (DLL4) downstream of vascular endothelial growth factor (VEGF). DLL4 subsequently activates Notch in the adjacent stalk cells suppressing sprouting. VEGF also activates A disintegrin and metalloproteases (ADAMs) that induce Notch ectodomain shedding.

The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses.

Immune cells regulate cell surface receptor expression during their maturation, activation, and motility. Although many of these receptors are regulated largely at the level of expression, protease-mediated ectodomain shedding represents an alternative means of refashioning the surface of immune cells. Shedding is largely attributed to a family of a disintegrin and metalloprotease domain (ADAM) metalloproteases, including ADAM17.

Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding.

Cellular senescence, a state of persistent cell cycle arrest, has emerged as a potent tumor suppressor mechanism by restricting proliferation of cells at risk for neoplastic transformation. Senescent cells secrete various growth factors, cytokines, and other proteins that can either elicit the clearance of tumor cells or potentially promote tumor progression. In addition, this senescence-associated secretory phenotype (SASP) includes various factors that are synthesized as transmembrane precursors and subsequently converted into their soluble counterparts.

A disintegrin and metalloprotease 17 dynamic interaction sequence, the sweet tooth for the human interleukin 6 receptor.

A disintegrin and metalloprotease 17 (ADAM17) is a major sheddase involved in the regulation of a wide range of biological processes. Key substrates of ADAM17 are the IL-6 receptor (IL-6R) and TNF-α. The extracellular region of ADAM17 consists of a prodomain, a catalytic domain, a disintegrin domain, and a membrane-proximal domain as well as a small stalk region.

Polo-like kinase 2, a novel ADAM17 signaling component, regulates tumor necrosis factor α ectodomain shedding.

ADAM17 (a disintegrin and metalloprotease 17) controls pro- and anti-inflammatory signaling events by promoting ectodomain shedding of cytokine precursors and cytokine receptors. Despite the well documented substrate repertoire of ADAM17, little is known about regulatory mechanisms, leading to substrate recognition and catalytic activation. Here we report a direct interaction of the acidophilic kinase Polo-like kinase 2 (PLK2, also known as SNK) with the cytoplasmic portion of ADAM17 through the C-terminal noncatalytic region of PLK2 containing the Polo box domains.

ADAM17 is a survival factor for microglial cells in vitro and in vivo after spinal cord injury in mice.

A disintegrin and metalloprotease 17 (ADAM17) is a sheddase with important substrates including tumor necrosis factor-α (TNF-α) and its receptors, the p75 neurotrophin receptor (p75NTR), and members of the epidermal growth factor family. The rationale of this study was to inhibit ADAM17-induced shedding of soluble TNF-α in order to reduce detrimental inflammation after spinal cord injury (SCI). However, using the specific ADAM17 blocker BMS-561392 in neuronal and glial cell cultures, we show that proper functioning of ADAM17 is vital for oligodendrocyte and microglia survival in a p44 MAPK-dependent manner.

Structural basis for inflammation-driven shedding of CD163 ectodomain and tumor necrosis factor-α in macrophages.

The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease ADAM17. This leads to release of soluble CD163 (sCD163) and bioactive TNF-α. Sequence comparison of the juxtamembrane region identified similar palindromic sequences in human CD163 ((1044)Arg-Ser-Ser-Arg) and proTNF-α ((78)Arg-Ser-Ser-Ser-Arg).

T-cell immunoglobulin and mucin domain 2 (TIM-2) is a target of ADAM10-mediated ectodomain shedding.

T-cell immunoglobulin and mucin domain (TIM)-2 is expressed on activated B cells. Here, we provide evidence that murine TIM-2 is a target of ADAM10-mediated ectodomain shedding, resulting in the generation of a soluble form of TIM-2. We identified ADAM10 but not ADAM17 as the major sheddase of TIM-2, as shown by pharmacological ADAM10 inhibition and with ADAM10-deficient and ADAM17-deficient murine embryonic fibroblasts.

Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells.

The "liver tolerance effect" has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10-dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A.

Short-term TNFα shedding is independent of cytoplasmic phosphorylation or furin cleavage of ADAM17.

Proteolysis of transmembrane molecules is an irreversible post-translational modification enabling autocrine, paracrine and endocrine signaling of many cytokines. The pro-inflammatory activities of membrane bound TNFα (pro-TNFα) strongly depend on ectodomain shedding mediated by the A Disintegrin And Metalloprotease family member ADAM17. Despite the well-documented role of ADAM17 in pro-TNFα cleavage during inflammation, little is known about its regulation.

Mouse neutrophils express the decoy type 2 interleukin-1 receptor (IL-1R2) constitutively and in acute inflammatory conditions.

The proinflammatory activities of IL-1 are tightly controlled at different levels. IL-1R2 acts as a decoy receptor and has been shown to regulate the biological effects of IL-1 in vitro and in vivo. However, little is known about its natural expression in the mouse in physiologic and pathologic conditions.

IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling.

The cytokine IL-6 plays a protective role in immune responses against bacterial infections. However, the mechanisms of IL-6-mediated protection are only partially understood. IL-6 can signal via the IL-6R complex composed of membrane-bound IL-6Rα (mIL-6Rα) and gp130.