Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies.
We addressed the impact of deleting TNF AU-rich elements (ARE) from the mouse genome on the regulation of TNF biosynthesis and the physiology of the host. Absence of the ARE affected mechanisms responsible for TNF mRNA destabilization and translational repression in hemopoietic and stromal cells. In stimulated conditions, TNF ARE were required both for the alleviation and reinforcement of message destabilization and translational silencing. Moreover, the mutant mRNA was no longer responsive to translational modulation by the p38 and JNK kinases, demonstrating that TNF ARE are targets for these signals. Development of two specific pathologies in mutant mice, i.e., chronic inflammatory arthritis and Crohn's-like inflammatory bowel disease, suggests that defective function of ARE may be etiopathogenic for the development of analogous human pathologies.
Kontoyiannis
D
D
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
Pasparakis
M
M
Pizarro
T T
TT
Cominelli
F
F
Kollias
G
G
D020413:3' Untranslated Regions / Q000235:genetics / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D001168:Arthritis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology; D003424:Crohn Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D003433:Crosses, Genetic; D005347:Fibroblasts / Q000378:metabolism; D006130:Growth Disorders / Q000235:genetics / Q000276:immunology / Q000401:mortality; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013583:Synovial Membrane / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D020413:3' Untranslated Regions; D015703:Antigens, CD; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases