A disintegrin and metalloproteinase 17 regulates TNF and TNFR1 levels in inflammation and liver regeneration in mice

Abstract

A disintegrin and metalloproteinase 17 (ADAM17), or tumor necrosis factor (TNF)-α-converting enzyme, is a key metalloproteinase and physiological convertase for a number of putative targets that play critical roles in cytokine and growth factor signaling. These interdependent pathways are essential components of the signaling network that links liver function with the compensatory growth that occurs during liver regeneration following 2/3 partial hepatectomy (PH) or chemically induced hepatotoxicity. Despite identification of many soluble factors needed for efficient liver regeneration, very little is known about how such ligands are regulated in the liver. To directly study the role of ADAM17 in the liver, we employed two cell-specific ADAM17 knockout (KO) mouse models. Using lipopolysaccharide (LPS) as a robust stimulus for TNF release, we found attenuated levels of circulating TNF in myeloid-specific ADAM17 KO mice (ADAM17 m-KO) and, unexpectedly, in mice with hepatocyte-specific ADAM17 deletion (ADAM17 h-KO), indicating that ADAM17 expression in both cell types plays a role in TNF shedding. After 2/3 PH, induction of TNF, TNFR1, and amphiregulin (AR) was significantly attenuated in ADAM17 h-KO mice, implicating ADAM17 as the primary sheddase for these factors in the liver. Surprisingly, the extent and timing of hepatocyte proliferation were not affected after PH or carbon tetrachloride injection in ADAM17 h-KO or ADAM17 m-KO mice. We conclude that ADAM17 regulates TNF, TNFR1, and AR in the liver, and its expression in both hepatocytes and myeloid cells is important for TNF regulation after LPS injury or 2/3 PH, but is not required for liver regeneration.

Metalloproteinases in liver fibrosis: current insights

“…ADAM17 mice deficient in myeloid lineage shed lower amount of TNFa after CCl 4 application compared to WT, leading to lower release of hepatocyte damage markers into serum. 91 However, since this disruption of TNFa signaling could not prevent liver damage as apoptosis and necrosis of hepatocytes were not altered in ADAM17 null mice, CCL 4 causes more complex reaction, which is not controlled by TNFa signaling.…”

“…Subsequently, only coordinated shedding of both, TNFa and TNFR, dictates outcome of the signaling. 91 In liver diseases, TNFa plays both protective and damaging roles. High levels of TNFa produced in liver after CCl 4 injection contribute to apoptosis of hepatocytes, 92 and neutralization with TNFa antibody showed to be beneficial in this type of injury.…”

“…Similarly, despite certain dysregulations, no major liver regeneration phenotypes were observed in mice with ADAM17 deficiency in either hepatocytes or Kupffer cells. 91 Regulation of the EGFR signaling by ADAMs in liver is complex and is not fully understood so far. One issue is certain redundancy between EGFR ligands, some of which can be cleaved not only by ADAM17 but also by other ADAMs, e.g., ADAM10 104 and ADAM12.…”

Deciphering the genomic toolkit underlying animal-bacteria interactions – insights through the demosponge Amphimedon queenslandica

“…Five members of the Metalloproteinase-disintegrins (ADAMs) family were upregulated by all three treatments at 2h. Two members of this family of enzymes are known to cleave and activate TNF ligands in humans (MezykKopec, et al 2009;McMahan, et al 2013). A single gene encoding a TNF receptor (TNFR) and two genes encoding TNF-receptor associated factors (TRAFs), the scaffold proteins linking TNFR to downstream signalling cascades (Aggarwal 2003), also were upregulated at 2h in all treatment groups (Fig.…”

“…However, its putative binding target -the TNF receptor -was more highly expressed in archaeocytes and pinacocytes (Table 4.1). In addition, five genes from the Metalloproteinase-disintegrins (ADAMs) family of metalloproteases, which could potentially cleave and activate the TNF ligands (Mezyk-Kopec, et al 2009;McMahan, et al 2013), were also more highly expressed in choanocytes (Table 4.1). Five genes encoding signalling scaffold proteins from the TNF receptor-associated factor (TRAF) family, which were downregulated across the three treatment groups in the feeding experiment, were more highly expressed in the choanocytes (Table 4.1).…”