Abstract
Endotoxin-stimulated blood cytokine responses have been widely used to describe compromised host defense mechanisms after trauma. We investigated whether blood cytokine production after endotoxin stimulation is able to define distinct trauma-induced alteration patterns and whether alteration patterns are associated with tumor necrosis factor (TNF) gene polymorphisms. In 48 patients undergoing joint replacement, the levels of TNF alpha (TNF-alpha), interleukin 6 (IL-6), and IL-8 production in blood after endotoxin stimulation were measured preoperatively on the day of surgery and 24 h thereafter. Patients were genotyped for the TNF-alpha position -308 G/A polymorphism and the TNF-beta NcoI polymorphism. Postoperative alterations, i.e., increases or decreases of cytokine levels (TNF-alpha versus IL-6, P = 0.013; TNF-alpha versus IL-8, P = 0.001; IL-6 versus IL-8, P = 0.007), and relative postoperative changes, i.e., percentages of preoperative cytokine levels (TNF-alpha versus IL-6, r(s) = 0.491, P < 0.001; TNF-alpha versus IL-8, r(s) = 0.591, P < 0.001; IL-6 versus IL-8, r(s) = 0.474, P < 0.001 [where r(s) is the Spearman rank correlation coefficient]), had significant positive correlations among the cytokines. Overall enhanced postoperative alteration patterns were found in 10 patients, attenuated patterns were found in 18 patients, and mixed patterns were found in 20 patients. Preoperative cytokine production levels differed significantly between these groups (those of the overall enhanced pattern group were less than those of the mixed pattern group, which were less than those of the overall attenuated pattern group). TNF polymorphisms were not associated with overall alteration patterns, but the A*TNFB1 haplotype was associated with a postoperative increase in TNF-alpha production (P = 0.042). Whole-blood cytokine responses to endotoxin define the following preexisting patterns in leukocyte function: low baseline production and overall enhanced alteration patterns after trauma (type 1), intermediate baseline production and mixed alteration patterns (type 2), and high baseline production and overall attenuated alteration patterns (type 3). TNF gene polymorphisms were associated with changes in TNF-alpha production but do not explain the overall reaction patterns of cytokine production after trauma. The clinical correlate of these newly defined reaction types remains to be determined.