Endotoxin response in spontaneously hypertensive rats: A role of the TNF alpha-gene region

We have shown previously that administration of endotoxin induces a smaller decrease of body temperature in spontaneously hypertensive rats (SHR) than in normotensive Brown Norway (BN) rats. Several studies have suggested tha t tumor necrosis factor alpha (TNF alpha) is one of the mediators of the bo dy-temperature response to endotoxin, To test whether the TNF alpha gene co uld be involved in determination of the observed difference in the body-tem perature response to endotoxin, we studied SHR (n = 6) and a congenic strai n, SHR.1N (n = 5), which differs from SHR by a segment of chromosome 20 ori ginating from BN and containing the TNF alpha gene. Body temperature was re corded continuously by means of radiotelemetry, We showed that, in both str ains, an intraperitoneal injection of endotoxin (500 mu g/kg of body weight ) induces a rapid hyperthermic phase (20-40 minutes post-injection), which is followed, first, by a hypothermic phase (100-120 minutes post-injection) and, then, by a late hyperthermic phase (seven hours). Although both strai ns demonstrated a similar trend in the response, a significant difference w as observed between the two response curves (P = 0.0001), Further analysis at each time point revealed that the two strains differed significantly at a peak of the hypothermic phase (P = 0.035) and the late hyperthermic phase (P = 0.035). In conclusion, these data indicate that the differential chro mosomal segment of SHR.1N contains a gene(s) causally related to the body-t emperature response to endotoxin. In the light of previously published data , the TNF alpha gene appears to be the most likely candidate gene within th e segment.