Abstract
Abstract Tumor necrosis factor (TNF) is produced by several immune cell types in response to injury or infection. A region on rat chromosome 4 regulates several inflammatory diseases including experimental autoimmune encephalomyelitis (EAE), experimental arthritis and experimental autoimmune neuritis. We hypothesized that central inflammatory processes may be controlled by genetic determinants in this region and therefore mapped TNF production using linkage analysis in an advanced intercross line between DA and PVG.AV1 rats. We identified a single TNF regulating quantitative trait locus with a LOD score of 6.16 and confirmed the biological effect in a congenic rat strain. Congenic strain macrophages produced less TNF upon lipopolysaccharide administration and subsequently had a reduced pro-inflammatory phenotype. The reduced TNF potential associated with reduced disease. Congenic rats had reduced EAE compared to control DA rats. We have identified genetically determined regulation of TNF, a central pro-inflammatory cytokine in many diseases. Determination of genes and mechanisms involved in this regulation will be valuable in pathological understanding and treatment development.
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