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PMID: 14769925 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 7 ·2004-02-17 ·Pages 2011-6

Phillips K, Kedersha N, Shen L, Blackshear PJ, Anderson P

Abstract

TIA-1 and TTP are AU-rich element-binding proteins that prevent the pathological overexpression of tumor necrosis factor alpha (TNF-alpha). TIA-1 inhibits the translation of TNF-alpha transcripts, whereas TTP promotes the degradation of TNF-alpha transcripts. Here we show that TIA-1 and TTP function as arthritis suppressor genes: TIA-1(-/-) mice develop mild arthritis, TTP(-/-) mice develop severe arthritis, and TIA-1(-/-)TTP(-/-) mice develop very severe arthritis. Peritoneal macrophages derived from all three genotypes overexpress cyclooxygenase 2 and TNF-alpha. Surprisingly, lipopolysaccharide-activated TIA-1(-/-)TTP(-/-) macrophages secrete less TNF-alpha protein than either TIA-1(-/-) or TTP(-/-) macrophages. In these mice, arthritogenic cytokine may be produced by neutrophils that accumulate in the bone marrow and peripheral blood. Our results suggest that TIA-1 and TTP are genetic modifiers of inflammatory arthritis that can alter the spectrum of cells that produce arthritogenic cytokines.

MeSH Terms
Animals Arthritis/genetics,pathology Bone Marrow Cells/drug effects,metabolism Cyclooxygenase 2 DNA-Binding Proteins Gene Deletion Gene Expression Regulation Genetic Predisposition to Disease Growth Immediate-Early Proteins/genetics,metabolism Isoenzymes/genetics,metabolism Lipopolysaccharides/pharmacology Macrophages, Peritoneal/drug effects,enzymology,metabolism Membrane Proteins/genetics,metabolism Mice Mice, Knockout Neutrophils/drug effects,metabolism Phenotype Prostaglandin-Endoperoxide Synthases/genetics,metabolism Proteins RNA, Messenger/genetics,metabolism RNA-Binding Proteins/genetics,metabolism T-Cell Intracellular Antigen-1 Tristetraprolin Tumor Necrosis Factor-alpha/genetics,metabolism
Chemicals
DNA-Binding Proteins Immediate-Early Proteins Isoenzymes Lipopolysaccharides Membrane Proteins Proteins RNA, Messenger RNA-Binding Proteins T-Cell Intracellular Antigen-1 Tia1 protein, mouse Tristetraprolin Tumor Necrosis Factor-alpha Zfp36 protein, mouse Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Phillips Kristine
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA.
Kedersha Nancy
Shen Lily
Blackshear Perry J
Anderson Paul
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0400148101
Published
2004-02-17
Epub
2004-00-09
Pages
2011-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC357043
Subset
IM
Grants
NIAID NIH HHS · R56 AI033600 · United States
NIAID NIH HHS · R01 AI033600 · United States
NIAID NIH HHS · AI33600 · United States
NIAID NIH HHS · R01 AI050167 · United States
NIAID NIH HHS · AI50167 · United States
External Links
PubMed source DOI: 10.1073/pnas.0400148101 PMC Full Text View journal details
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