Sedative Drug Modulates T-Cell and Lymphocyte Function-Associated Antigen-1 Function

Department of Anesthesiology, Pain and Perioperative Medicine, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115, USA.
Anesthesia and analgesia (Impact Factor: 3.47). 03/2011; 112(4):830-8. DOI: 10.1213/ANE.0b013e31820dcabb
Source: PubMed


Sedative drugs modify immune cell functions via several mechanisms. However, the effects of sedatives on immune function have been primarily investigated in neutrophils and macrophages, and to the lesser extent lymphocytes. Lymphocyte function-associated antigen-1 (LFA-1) is an adhesion molecule that has a central role in regulating immune function of lymphocytes including interleukin-2 (IL-2) production and lymphocyte proliferation. Previous clinical studies reported that propofol and isoflurane reduced IL-2 level in patients, but midazolam did not. We previously demonstrated that isoflurane inhibited LFA-1 binding to its counter ligand, intercellular adhesion molecule-1 (ICAM-1), which might contribute to the reduction of IL-2 levels. In the current study, we examined the effect of propofol, midazolam, and dexmedetomidine on LFA-1/ICAM-1 binding, and the subsequent biological effects.
The effect of sedative drugs on T-cell proliferation and IL-2 production was measured by calorimetric assays on human peripheral blood mononuclear cells. Because LFA-1/ICAM-1 binding has an important role in T-cell proliferation and IL-2 production, we measured the effect of sedative drugs on ICAM-1 binding to LFA-1 protein (cell-free assay). This analysis was followed by flow cytometric analysis of LFA-1 expressing T-cell binding to ICAM-1 (cell-based assay). To determine whether the drug/LFA-1 interaction is caused by competitive or allosteric inhibition, we analyzed the sedative drug effect on wild-type and high-affinity LFA-1 and a panel of monoclonal antibodies that bind to different regions of LFA-1.
Propofol at 10 to 100 μM inhibited ICAM-1 binding to LFA-1 in cell-free assays and cell-based assays (P < 0.05). However, dexmedetomidine and midazolam did not affect LFA-1/ICAM-1 binding. Propofol directly inhibits LFA-1 binding to ICAM-1 by binding near the ICAM-1 contact area in a competitive manner. At clinically relevant concentrations, propofol, but not dexmedetomidine or midazolam, inhibited IL-2 production (P < 0.05). Additionally, propofol inhibited lymphocyte proliferation (P < 0.05).
Our study suggests that propofol competitively inhibits LFA-1 binding to ICAM-1 on T-cells and suppresses T-cell proliferation and IL-2 production, whereas dexmedetomidine and midazolam do not significantly influence these immunological assays.

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    • "pheral blood, and proliferation of T cells in spleen during endotoxemia. V C 2014 Wiley Periodicals , Inc. Environ INTRODUCTION Currently, sedation - related immune effects are important issues under investigation as recent studies showed that seda - tive agents modulate immune functions ( Leonard and Red - mond , 2003 ; Kurosawa and Kato , 2008 ; Yuki et al . , 2011 ) . However , while many studies on the effects of other common sedatives on the immune system had been conducted , there is little and inconsistent evidence on how dexmedetomidine ( dex ) affects immune functions at different tissue levels . There is a recent randomized controlled trial revealing the protective effect of dex against se"
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    • "ICAM-1 is the major endogenous ligand for LFA-1. A cell-based LFA-1: ICAM-1 binding assay was performed using flow cytometry as previously described [23]. Briefly, 293 T cells transiently transfected with LFA-1 were harvested in HBS containing 10 mM EDTA 48 hours after transfection. "
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