Procalcitonin and proinflammatory cytokine interactions in sepsis

Immunoneutralization of procalcitonin (ProCT), a putative mediator of sepsi s, has been shown to increase survival in an animal model of sepsis. To bet ter understand the role that ProCT plays in the sepsis cascade, we studied the relationship of this hormone to the proximal proinflammatory mediators, IL-1 beta and TNF alpha. Hamsters were made septic by i.p. implantation of Escherichia coli-impregnated agar pellets. A time line study of serum IL-1 beta, TNF alpha, and ProCT levels showed that the increase in the cytokine s was transient and less than 2-fold over baseline, whereas ProCT increased >100-fold by 12 h and remains elevated through 24 h. TNF alpha (400 mu g/k g) was injected into healthy animals, inducing an elevation in ProCT that w as 25-fold greater than controls. ProCT (30 mu g/kg) was given to healthy a nd septic animals. In healthy animals, there was no significant elevation i n serum IL-1 beta or TNF alpha levels. In septic animals, IL-1 beta was mod estly blunted at 3 h but not at 12 h, and there was no change in TNF alpha levels. ProCT did not initiate or enhance IL-l beta or TNF alpha expression ; however, the massive and sustained elevation of this hormone seen in seps is can be induced by the proximal cytokine, TNF alpha. This study suggests that ProCT is a secondary mediator that might augment and amplify but does not initiate the septic response. Immunoneutralization of ProCT may prove t o be an important clinical strategy, in view of its sustained elevation and the difficulty in initiating therapy for sepsis during the early phases of illness.