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

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          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.

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          Author and article information

          Journal
          Am. J. Physiol. Gastrointest. Liver Physiol.
          American journal of physiology. Gastrointestinal and liver physiology
          American Physiological Society
          1522-1547
          0193-1857
          Jul 01 2013
          : 305
          : 1
          Affiliations
          [1 ] Department of Pathology, University of Washington, Seattle, WA 98195, USA.
          Article
          ajpgi.00326.2012
          10.1152/ajpgi.00326.2012
          3725689
          23639813
          1b9f92cf-0376-4e81-8042-34e396268734
          History

          tumor necrosis factor receptor,amphiregulin,lipopolysaccharide,partial hepatectomy,tumor necrosis factor-α converting enzyme

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