title: TNF production in macrophages is genetically determined and regulates inflammatory disease in rats.
abstract: 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.
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. alan.gillett@ki.se
authors.forename: Alan
authors.initials: A
authors.lastname: Gillett
authors.forename: Monica
authors.initials: M
authors.lastname: Marta
authors.forename: Tao
authors.initials: T
authors.lastname: Jin
authors.forename: Jonatan
authors.initials: J
authors.lastname: Tuncel
authors.forename: Patrick
authors.initials: P
authors.lastname: Leclerc
authors.forename: Rita
authors.initials: R
authors.lastname: Nohra
authors.forename: Stefan
authors.initials: S
authors.lastname: Lange
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D016130:Immunophenotyping / Q000379:methods; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009444:Neuritis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020161:Physical Chromosome Mapping; D040641:Quantitative Trait Loci / Q000276:immunology; D051381:Rats; D018805:Sepsis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013729:Terpenes / Q000633:toxicity; D051193:Toll-Like Receptors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D013729:Terpenes; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C009042:pristane