Roles of tumor necrosis factor-alpha receptor subtypes in the pathogenesis of the tristetraprolin-deficiency syndrome.
Tristetraprolin (TTP) is a member of the CCCH tandem zinc-finger class of proteins. It can bind to and destabilize mRNAs encoding tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, mice deficient in TTP develop a complex syndrome characterized by cachexia, myeloid hyperplasia, and joint and skin inflammation. Studies using anti-TNF-alpha neutralizing antibodies demonstrated that this syndrome, at least in part, is a consequence of the excess production of TNF-alpha in the absence of TTP. To evaluate the role played by each TNF-alpha receptor in the pathogenesis of this syndrome, mice were generated that were deficient in TTP and either or both of the known TNF-alpha receptors (TNFRs), type 1 (TNFR1) and type 2 (TNFR2). Mice deficient in TTP and TNFR1, or in TTP and both receptors, were protected from developing the TNF-alpha-induced cachexia and inflammation. In contrast, mice deficient in TNFR2 were more severely affected than mice deficient in TTP alone, suggesting that TNFR2 might play a protective role in the development of the syndrome. In cultured cells derived from these mice, apparent cooperation between the TNFRs was required to achieve normal TNF-alpha-induced expression of TTP, TNF-alpha, and GM-CSF mRNAs. Finally, the results showed that TNFR1 plays an important role in mediating TNF-alpha-induced changes in TNF-alpha and GM-CSF mRNA stability.
Carballo
E
E
Office of Clinical Research and Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Blackshear
P J
PJ
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006580:Genetic Carrier Screening; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013577:Syndrome; D014158:Transcription, Genetic; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016335:Zinc Fingers
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; C497553:Zfp36 protein, mouse