NCBI Logo
GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
          Go
Series GSE53835 Query DataSets for GSE53835
Status Public on May 30, 2014
Title Pathological activation of canonical nuclear-factor kB by synergy of tumor necrosis factor alpha and TNF-like weak inducer of apoptosis in mouse acute colitis
Organism Mus musculus
Experiment type Expression profiling by array
Summary To test the efficacy of TNFR-Fc and anti-TWEAK mAb treatment alone and in combination
Tumor necrosis factor (TNF)-alpha is a major effector in various inflammatory conditions. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that promotes inflammatory tissue damage through its receptor, FGF-inducible molecule 14 (Fn14). Since both TWEAK and TNF-alpha have been shown to mediate pathological responses through inter-dependent or independent pathways by in vitro, the potential interplay of these pathways was investigated in a mouse colitis model. Acute colitis was induced by rectal injection of trinitrobenzene sulfonic acid (TNBS), with administration of control IgG, TNF receptor (TNFR)-Ig chimeric protein, anti-TWEAK monoclonal antibody, or the combination of TNFR-Ig and anti-TWEAK antibody. On day 4, disease severity was evaluated and gene expression profiling was analyzed using whole colon tissue. Levels of transcript of TWEAK, Fn14 and NF-kB-related molecules were measured in purified colon epithelial cells (ECs). NF-kB activation was investigated with Western blot and immunohistochemical analysis. As a result, activation of the canonical, but not noncanonical NF-kB pathway was the hallmark of inflammatory responses in this model. Inflammation induced upregulation of Fn14 only in ECs but not in other cell types. Combination treatment of TNFR-Ig and anti-TWEAK antibody synergistically reduced disease severity in comparison with the control antibody or single agent treatment. Gene expression profile of the colon indicated downregulation of canonical NF-kB pathway with combination treatment. In conclusion, synergistic activation of canonical NF-kB by TWEAK and TNF-alpha is critical for the induction of inflammatory tissue damage in acute inflammation.
 
Overall design TNBS colitis was induced by intrarectal administration of a 2 % solution of TNBS in phosphate-buffered saline (PBS): ethanol (1:1). For acute inflammatory responses, 70 μg/g body weight of TNBS was given on day 0 and animals sacrificed on day 4. One hour prior to administration of TNBS, groups of mice were injected i.p. with the control IgG2a mAb (anti-human CD20) (10 mg/kg), TNFR-Ig (0.3 mg/kg), anti-TWEAK (mP2D10, 10 mg/kg), the combination of TNFR-Fc (0.3 mg/kg) and anti-TWEAK mP2D10 (10 mg/kg), or were untreated. For single agent and combination treatments groups, 0.3 mg/kg TNFR-Ig was employed, since 1 mg/kg of TNFR-Ig markedly ameliorated TNBS colitis but 0.3 mg/kg was much less effective as monitored by the effect on colon length and body weight. Colon tissue was rolled and snap-frozen in liquid nitrogen. Specimens for RNA extraction were cut from the frozen rolled colon. A set of experiments using 5-8 mice for each experimental group was performed twice, labelled 7 and 10 in the CEL files. Total number of mice for each experimental condition was as follows; untreated TNBS colitis group, 8; control antibody, 15; TNFR-Ig, 12; anti-TWEAK mAb, 14; combination of TNFR-Ig and anti-TWEAK mAb, 15.
 
Contributor(s) Burkly LC, Dohi T
Citation missing Has this study been published? Please login to update or notify GEO.
Submission date Jan 06, 2014
Last update date Feb 11, 2019
Contact name Suzanne Szak
Organization name BiogenIdec, Inc.
Department Drug Discovery
Street address 14 Cambridge Ctr
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (72)
GSM1301786 Disease_No_treat_Comb7_1
GSM1301787 Disease_No_treat_Comb7_2
GSM1301788 Disease_No_treat_Comb7_3
Relations
BioProject PRJNA233496

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE53835_RAW.tar 276.1 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap