RGD Reference Report - TNF production in macrophages is genetically determined and regulates inflammatory disease in rats. - Rat Genome Database

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TNF production in macrophages is genetically determined and regulates inflammatory disease in rats.

Authors: Gillett, A  Marta, M  Jin, T  Tuncel, J  Leclerc, P  Nohra, R  Lange, S  Holmdahl, R  Olsson, T  Harris, RA  Jagodic, M 
Citation: Gillett A, etal., J Immunol. 2010 Jul 1;185(1):442-50. doi: 10.4049/jimmunol.0904101. Epub 2010 May 26.
RGD ID: 8662331
Pubmed: PMID:20505148   (View Abstract at PubMed)
DOI: DOI:10.4049/jimmunol.0904101   (Journal Full-text)

Dysregulation of TNF is an important pathophysiological phenotype for many diseases. Recently, certain genetically regulated loci have been identified to regulate several inflammatory diseases. We hypothesized that a region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis, experimental arthritis and experimental autoimmune neuritis harbors a gene regulating central inflammatory molecules, such as TNF. We therefore mapped TNF production using linkage analysis in the 12th generation of an advanced intercross line between DA and PVG.AV1 rats, which differ in susceptibility to several inflammatory conditions. A single TNF-regulating quantitative trait locus with a logarithm of odds score of 6.2 was identified and its biological effect was confirmed in a congenic rat strain. The profound TNF regulation mapped in congenic strains to the macrophage population. Several TLR signaling cascades led to the same reduced proinflammatory phenotype in congenic macrophages, indicating control of a convergence point for innate inflammatory activity. The decreased TNF potential and reduced proinflammatory macrophage phenotype in congenic rats was also associated with reduced clinical severity in experimental autoimmune encephalomyelitis, pristane-induced arthritis and sepsis experimental models. Determination of genes and mechanisms involved in this genetically determined TNF regulation will be valuable in understanding disease pathogenesis and aid treatment development.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
arthritis  IAGP 8662331 RGD 
Experimental Autoimmune Encephalomyelitis  IAGP 8662331 RGD 
Experimental Autoimmune Neuritis  IAGP 8662331 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
CNS inflammation  IDA 8662331 RGD 
Objects Annotated

Eae35  (Experimental allergic encephalomyelitis QTL 35)

Objects referenced in this article
Strain DA.PVG.1AV1-(D4Got60-D4Kini1)/Kini null Rattus norvegicus
Strain DA.PVG.1AV1-(D4Rat103-D4Mit12)/Kini null Rattus norvegicus

Additional Information