Open AccessLpsd/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses
Author(s) -
Pierre Wong,
Anthony D. Kang,
Hong Chen,
Quan Yuan,
Peidong Fan,
Barnet M. Sultzer,
Yuet Wai Kan,
Siu-Wah Chung
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.20.11543
Subject(s) - complementary dna , microbiology and biotechnology , lipopolysaccharide , mutant , biology , gene , ran , immunology , biochemistry
C3H/HeJ inbred mice are defective in that they are highly resistant to endotoxic shock as compared with normal responder mice. Their B cells and macrophages do not respond significantly when exposed to lipopolysaccharide (LPS), whereas cells from the responder mice do. Using a functional assay, we previously isolated a cDNA, which encodes for Ran/TC4 GTPase. We now show that this gene is mutated in C3H/HeJ mice, which accounts for their resistance to endotoxin stimulation. Sequence analysis of independent mutant Lpsd /Ran cDNAs isolated from splenic B cells of C3H/HeJ mice reveals a consistent single base substitution at position 870, where a thymidine is replaced with a cytidine.In situ hybridization maps the Lpsd /Ran cDNA to mouse chromosome 4. By retroviral gene transfer, the wild-type Lpsn /Ran cDNA but not the mutant Lpsd /Ran cDNA can restore LPS responsiveness of C3H/HeJ cells. Adenoviral gene transferin vivo with the mutant Lpsd /Ran cDNA but not the wild-type Lpsn /Ran cDNA rescues endotoxin-sensitive mice from septic shock. Thus Lps/Ran is an important target for LPS-mediated signal transduction, and theLpsd /Ran gene may be useful as a therapeutic sequence in gene therapy for endotoxemia and septic shock.