A Role for cGMP in Inducible Nitric-oxide Synthase (iNOS)-induced Tumor Necrosis Factor (TNF) α-converting Enzyme (TACE/ADAM17) Activation, Translocation, and TNF Receptor 1 (TNFR1) Shedding in Hepatocytes

Abstract

Background: iNOS/NO blocks TNF␣-induced apoptosis by cGMP-dependent and cGMP-independent mechanisms in hepatocytes. Result: TLR4-dependent iNOS expression in hepatocytes leads to NO/cGMP/PKG-dependent TACE/ADAM17 and iRhom2 phosphorylation and interaction, TACE/ADAM17 activation/surface translocation, and TNFR1 shedding. Conclusion: iNOS expression leads to rapid TNFR1 shedding through NO/cGMP/PKG-dependent translocation and activation of TACE/ADAM17. Significance: This novel mechanism for iNOS/NO/cGMP-induced TACE activation and translocation may limit TNF␣-mediated signaling.

Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling

“…We previously showed that HC-TNFR1 shedding is stimulated by the TLR4 ligand lipopolysaccharide (LPS) in vitro and in vivo (10); however, during polymicrobial sepsis, multiple TLR ligands and cytokines are involved in propagating the inflammatory response. To determine the mechanisms involved in a clinically relevant polymicrobial sepsis model, we assessed TNFR1 shedding in mice during sepsis induced by cecal ligation and puncture (CLP).…”

“…We previously showed that HC-TNFR1 shedding is mediated by iNOS (10). Therefore, we postulated that iNOS might be downstream of MyD88 in the regulation of TNFR1 shedding during sepsis.…”

“…TNFR1 is found on immune cells, such as macrophages (8), and parenchymal cells, such as hepatocytes (9). Excessive activation of TNFR1 by TNF leads to the apoptosis of hepatocytes, and thus leads to organ damage (9); however, membrane-bound TNFR1 can be cleaved through proteolytic shedding of its ectodomain, which is dependent on activation of TNF-converting enzyme (TACE, also known as ADAM17) (10). Receptor shedding is thought to be protective by reducing cellular responses to TNF and by binding to and sequestering extracellular TNF.…”

A Disintegrin and Metalloprotease 17 Dynamic Interaction Sequence, the Sweet Tooth for the Human Interleukin 6 Receptor

“…In addition, the soluble TNFRI ectodomain acts as an antagonist of TNF-␣ signaling mediated by its membrane-bound form. Both effects result in immunosuppressive and antiapoptotic properties of TNFRI shedding (13,14). In clear contrast, shedding of IL-6R leads to the generation of an agonist of IL-6-mediated signaling, the soluble IL-6R (sIL-6R).…”

“…For example, shedding of proTNF-␣ leads to the generation of the actual proinflammatory, soluble cytokine. Cleavage of the TNFRI decreases the TNF-␣ sensitivity of cells expressing the respective receptor, such as monocytes, macrophages, and hepatocytes (12)(13)(14). In addition, the soluble TNFRI ectodomain acts as an antagonist of TNF-␣ signaling mediated by its membrane-bound form.…”