Document Detail


iRHOM2 is a critical pathogenic mediator of inflammatory arthritis.
MedLine Citation:
PMID:  23348744     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-α convertase (TACE), which controls shedding of TNF-α and its biological activity in vivo. TACE is a potential target to treat TNF-α-dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. Here we report that inactivation of Rhbdf2 allows tissue-specific regulation of TACE by selectively preventing its maturation in immune cells, without affecting its homeostatic functions in other tissues. The related iRHOM1, which is widely expressed, except in hematopoietic cells, supported TACE maturation and shedding of the EGFR ligand TGF-α in Rhbdf2-deficient cells. Remarkably, mice lacking Rhbdf2 were protected from K/BxN inflammatory arthritis to the same extent as mice lacking TACE in myeloid cells or Tnfa-deficient mice. In probing the underlying mechanism, we found that two main drivers of K/BxN arthritis, complement C5a and immune complexes, stimulated iRHOM2/TACE-dependent shedding of TNF-α in mouse and human cells. These data demonstrate that iRHOM2 and myeloid-expressed TACE play a critical role in inflammatory arthritis and indicate that iRHOM2 is a potential therapeutic target for selective inactivation of TACE in myeloid cells.
Authors:
Priya Darshinee A Issuree; Thorsten Maretzky; David R McIlwain; Sébastien Monette; Xiaoping Qing; Philipp A Lang; Steven L Swendeman; Kyung-Hyun Park-Min; Nikolaus Binder; George D Kalliolias; Anna Yarilina; Keisuke Horiuchi; Lionel B Ivashkiv; Tak W Mak; Jane E Salmon; Carl P Blobel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-11-13    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  928-32     Citation Subset:  AIM; IM    
Affiliation:
Arthritis and Tissue Degeneration Program, Autoimmunity and Inflammation Program, Hospital for Special Surgery, Weill Cornell University, New York, New York, USA.
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MeSH Terms
Descriptor/Qualifier:
ADAM Proteins / deficiency,  genetics,  physiology
Adaptor Proteins, Signal Transducing / physiology
Animals
Arthritis, Experimental / etiology*,  immunology,  physiopathology
Arthritis, Rheumatoid / etiology,  immunology,  physiopathology
Carrier Proteins / genetics,  physiology*
Humans
LIM Domain Proteins / physiology
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, Transgenic
Proto-Oncogene Proteins / physiology
Receptor, Epidermal Growth Factor / physiology
Signal Transduction
Tumor Necrosis Factor-alpha / deficiency,  genetics,  physiology
Grant Support
ID/Acronym/Agency:
AR050401/AR/NIAMS NIH HHS; AR061430/AR/NIAMS NIH HHS; AR38889/AR/NIAMS NIH HHS; K99 AR061430/AR/NIAMS NIH HHS; LA2558/3-1//PHS HHS; R01 AR046713/AR/NIAMS NIH HHS; R01 GM064750/GM/NIGMS NIH HHS; R01 GM64750/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Carrier Proteins; 0/LIM Domain Proteins; 0/LMO2 protein, human; 0/Proto-Oncogene Proteins; 0/Tumor Necrosis Factor-alpha; 0/iRhom2 protein, mouse; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/tumor necrosis factor-alpha convertase
Comments/Corrections
Comment In:
J Clin Invest. 2013 Feb 1;123(2):560-2   [PMID:  23348732 ]

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