Physically active rats have facilitated heat shock protein 72 (Hsp72) responses following stressor exposure in both brain and peripheral tissues compared to sedentary rats (11). This study verifies that physically active animals do not have elevated Hsp72 levels compared to sedentary animals in the hypothalamus, pituitary, or dorsal vagal complex. We then examined if 1) physically active rats respond more efficiently than sedentary rats to a bacterial challenge; 2) peripheral immune challenge elicits brain induction of Hsp72; 3) this induction is facilitated by prior freewheel running; and, 4) Hsp72 up-regulation produced by peripheral immune challenge results in a commensurate decrease in the pro-inflammatory cytokine interleukin 1 beta (IL-1). Adult male Fischer 344 rats were housed with either a mobile or locked running wheel (Sed). Six weeks later, rats were injected (ip) with saline or Escherichia coli (E.coli) and sacrificed 30 min, 2.5 hr, 6 hr, and 24 hr later. Serum endotoxin (LAL) and IL-1, and peritoneal fluid endotoxin and E.coli colony forming units (CFU) were measured. Hsp72 and IL-1 were measured in hypothalamus, pituitary, and dorsal vagal complex. The results were that physically active rats had a faster reduction in endotoxin and E.coli CFU and lower levels of circulating endotoxin and cytokines compared to sedentary rats. E.coli challenge elicited significantly greater time-dependent increases of both Hsp72 and IL-1 in hypothalamus, pituitary and dorsal vagal complex of physically active animals but not sedentary animals. Contrary to our hypothesis, increases in Hsp72 were positively correlated with IL-1. This study extends our findings that physical activity facilitates stress-induced Hsp72 to include immunological stressors such as bacterial challenge and suggests that brain Hsp72 and IL-1 responses to peripheral immune challenge may contribute to exercise-mediated resistance to long-term sickness.