Abstract
The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are not viable. Conditional ADAM17 knockout models demonstrated proinflammatory activities of ADAM17 in septic shock via shedding of TNF. We used a novel gene targeting strategy to generate mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17(ex/ex) were viable, showed compromised shedding of ADAM17 substrates from the cell surface, and developed eye, heart, and skin defects as a consequence of impaired EGF-R signaling caused by failure of shedding of EGF-R ligands. Unexpectedly, although the intestine of unchallenged homozygous ADAM17(ex/ex) mice was normal, ADAM17(ex/ex) mice showed substantially increased susceptibility to inflammation in dextran sulfate sodium colitis. This was a result of impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and, consequently, in defective regeneration of epithelial cells and breakdown of the intestinal barrier. Besides regulating the systemic availability of the proinflammatory cytokine TNF, our results demonstrate that ADAM17 is needed for vital regenerative activities during the immune response. Thus, our mouse model will help investigate ADAM17 as a potential drug target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / deficiency
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM17 Protein
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Animal Structures / abnormalities
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Animal Structures / metabolism
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Animals
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Brain / metabolism
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Cell Proliferation / drug effects
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Chemokines / metabolism
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Colon / metabolism
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Colon / pathology
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Cyclin D1 / metabolism
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Cytokines / metabolism
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Dextran Sulfate / pharmacology
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Female
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Gene Expression / genetics
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Gene Expression Profiling
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Inflammatory Bowel Diseases / chemically induced
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Inflammatory Bowel Diseases / enzymology
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Inflammatory Bowel Diseases / immunology*
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Inflammatory Bowel Diseases / pathology*
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Intestinal Mucosa / enzymology
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / pathology*
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Intestinal Mucosa / physiology
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L-Selectin / metabolism
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Liver / metabolism
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Mammary Glands, Animal / growth & development
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Permeability
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Peroxidase / metabolism
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Phosphorylation / drug effects
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Receptors, Tumor Necrosis Factor, Type II / blood
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Regeneration*
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STAT3 Transcription Factor / metabolism
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Transforming Growth Factor alpha / metabolism
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Transforming Growth Factor alpha / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Ccnd1 protein, mouse
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Chemokines
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Cytokines
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Receptors, Tumor Necrosis Factor, Type II
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Transforming Growth Factor alpha
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Tumor Necrosis Factor-alpha
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L-Selectin
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Cyclin D1
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Dextran Sulfate
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Peroxidase
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ADAM Proteins
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ADAM17 Protein
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Adam17 protein, mouse