Is interferon gamma suppression after cardiac surgery caused by a decreased interleukin-12 synthesis?

BACKGROUND: The suppression of interferon gamma (IFN-gamma) synthesis after cardiac surgery is discussed as a cause of postoperative immunosuppression that predisposes to postoperative infectious complications. Because several studies have suggested that interleukin-12 (IL-12) production by monocytes and macrophages is reduced after cardiac surgery, this might cause a decrease in IFN-gamma release. To better understand these processes, we assessed the role of IL-12 in IFN-gamma synthesis in vitro before and after cardiac surgery. METHODS: Heparinized whole blood samples were obtained from 20 patients undergoing elective cardiac surgery preoperatively (day 0) and on the first (day 1), third (day 3), and fifth (day 5) postoperative days, and stimulated (24 hours) with staphylococcal enterotoxin B and lipopolysaccharide. Recombinant IL-12 was added at each time point investigated. Interferon-gamma, IL-12, IL-2, IL-4, and IL-5 concentrations and histocompatibility leukocyte antigen-DR (HLA-DR) expression on monocytes and macrophages were assayed by flow cytometry. RESULTS: The HLA-DR expression, IL-12 release, and IFN-gamma synthesis were significantly reduced on day 1, day 3, and day 5. Recovery began on day 3. Interleukin-12 caused a significant increase in IFN-gamma synthesis at each time point. When IL-12 was added, IFN-gamma synthesis returned to preoperative levels on days 3 and 5. CONCLUSIONS: The synthesis of IFN-gamma is significantly reduced after cardiac surgery. The application of IL-12 causes an increase in IFN-gamma synthesis before surgery and a return of IFN-gamma to preoperative levels within a few days after surgery. These findings suggest that postoperative suppression of IFN-gamma release is caused by a decrease in IL-12 synthesis. In addition, IL-12 has a mainly proinflammatory effect both before and after surgery.

Hyporesponsiveness of T cell subsets after cardiac surgery: a product of altered cell function or merely a result of absolute cell count changes in peripheral blood?

OBJECTIVE: The activity of the specific immune system and especially the function of T helper (TH) cells are reduced after cardiac surgery. This decrease is followed by an increase in TH2 cell activity and a delayed recovery of TH1 cell function (TH1/TH2 shift). Neither the underlying cause nor the relationship between the absolute numbers of T lymphocyte subpopulations, the state of activation of these cells and cytokine synthesis in cell culture has been clarified. We conducted a prospective study in order to test the hypothesis that the decrease in specific immunity is not caused by dilution effects but by functional alterations in T cell subsets. METHODS: Blood samples were obtained from 40 patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) preoperatively (d0), immediately after surgery (dx), and on the 1st (d1), 3rd (d3) and 5th (d5) postoperative days. The samples were stimulated for 24h with staphylococcal enterotoxin B and lipopolysaccharide. Interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-5 concentrations were measured by flow cytometry using a cytokine bead array kit. We determined white blood cell counts, analysed lymphocyte populations, and assayed human leukocyte antigen (HLA)-DR expression on cluster of differentiation (CD)4+ and CD8+ lymphocytes. Cytokine concentrations were corrected to preoperative absolute numbers of T helper cells. RESULTS: Leukocyte counts were elevated during the entire postoperative course with a maximum on dx. Absolute lymphocyte counts and especially the T cell subpopulations significantly increased immediately after surgery, then decreased to a minimum on d1 and increased again until they returned to preoperative levels on d3. The release of IFN-gamma, IL-2 and IL-4 was significantly reduced from dx to d5 with a minimum on d1. IL-5 was significantly reduced on dx and d1. When the concentrations were corrected to preoperative TH lymphocyte levels, IL-2 and IL-5 synthesis was significantly reduced only on dx and IL-4 release only on dx and d1. By contrast, IFN-gamma synthesis decreased postoperatively and remained suppressed until d5 with a minimum on d1. Only on d1 did an increase in HLA-DR expression give evidence of a change in the state of TH cell activation. CONCLUSIONS: The number of immune cells of the specific and the non-specific immune system is not reduced in the immediate postoperative period. Haemodilution thus has no detectable effect on immune function at this time point. Beginning on d1, the function of specific immune cells, especially TH lymphocytes, is severely suppressed. This functional alteration appears not to be preceded by T cell activation during CPB. Although TH cell activity begins to increase on d1, cytokine synthesis is reduced. When cytokine synthesis is corrected to the absolute number of TH cells in culture, there is strong evidence for an increase in TH2 cell activity. On the whole, these results corroborate the hypothesis of a TH1/TH2 shift that is primarily caused by an alteration of TH1 function. Neither haemodilution nor a preceding activation plays a major role.

Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: is what we see what we know?

OBJECTIVE: Due to the combination of local trauma, extracorporeal circulation (ECC), and pulmonary and myocardial reperfusion, cardiac surgery leads to substantial changes in the immune system and possibly to post-operative complications. Procedures without ECC, however, have failed to demonstrate clear advantages. We hypothesized that ECC is far less important in this context than the reperfusion/reventilation of the lung parenchyma and the surgical trauma. We therefore conducted a prospective observational study to compare immune reactions after cardiac operations with those after thoracic surgery. METHODS: Serum levels of pro-inflammatory interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha as well as C-reactive protein (CRP), lipoprotein-binding protein (LBP) and procalcitonin (PCT) were measured pre-operatively (d0), at the end of the operation (dx), 6h after the operation (dx+), on the 1st (d1), 3rd (d3), and 5th (d5) post-operative days in 108 patients (pts) undergoing elective coronary artery bypass grafting (CAB) with ECC (n=42, CPB CAB), off-pump coronary artery bypass surgery (n=24, OP CAB) without ECC or thoracic surgery (n=42, TS). RESULTS: After cardiac surgery (CS), IL-6 and IL-8 increased and reached a maximum on dx+. IL-6 returned to baseline values at d3, whereas IL-8 remained elevated until d5. No difference was found between OP CAB and CPB CAB patients. In the TS patients, IL-6 increased later (dx+) and absolute levels were lower than in the CS patients. No increase in IL-8 was noted in the TS patients. Due to the high variation in the results obtained in all three groups, there was no significant change in TNF-alpha. A comparison of TS, OP CAB, and CPB CAB revealed that the CS patients had higher levels on d0, dx, d3, and d5. Serum levels of CRP, LBP, and IL-2R increased from dx+ to d5 in all groups and reached maximum values on d3. Whereas we found no difference in CRP and IL-2R between the groups, LBP levels were significantly higher from dx+ to d3 after OP CAB. PCT was elevated from dx+ to d3 in all pts. Similar levels were noted for the TS and OP CAB patients. The CPB CAB patients showed the highest levels. CONCLUSIONS: Surgical trauma and reperfusion injury appear to represent the predominant factors resulting in immunologic changes after cardiac surgery. Cardiopulmonary bypass (CPB) may be less important for immune response and acute-phase reactions than previously suspected. In addition, our data indicate a relationship between IL-6 synthesis and the degree of surgical trauma. IL-8 appears to be elevated only after cardiac surgery whereas PCT liberation depended on the use of ECC.