Identification of rat quantitative trait loci that regulate LPS-induced pro-inflammatory cytokine responses

Bacterial lipopolysaccharides (LPSs) trigger innate immune effector functions, such as the production of pro-inflammatory cytokines. Here we utilized major histocompatibility complex (MHC)-congenic rats to dissect the genetic basis of strain-dependent variations of LPS-induced tumour necrosis factor-alpha (TNF-alpha) levels in a whole blood in vitro assay. PVG.1AV1 background was associated with a high response, ACI background with a medium response, and LEW.1AV1 and DA backgrounds were associated with low responses. To determine the location of regulating non-MHC genes, a genome-wide linkage analysis with 236 microsatellite markers was performed on 186 F2 progeny of high TNF-alpha responder PVG.1AV1 and MHC identical but low TNF-alpha responder LEW.1AV1 rats. A region on rat chromosome 1 displayed linkage to LPS-induced TNF-alpha responses (P = 3.3 x 10-5). In addition, a locus on chromosome 2 was linked to responses of both interleukin-6 (IL-6) (P = 2.3 x 10-5) and TNF-alpha (possible linkage, P = 8 x 10-3). Both chromosome regions have been linked to inflammatory diseases in rats, and so have the homologous regions in mice and humans. We therefore suggest that continued genetic dissection of the described in vitro phenotypes will give clues to both normal physiological regulation of LPS-induced TNF-alpha production and disease pathways.