Effects of Anaesthetic Agents on White Cell Function

Dr Dan Wheeler, Cambridge, UK

Leucocytes migrate from the bloodstream to the site of inflammation in response to a complex network of pro-inflammatory signaling molecules including chemokines, cytokines and prostaglandins. A very wide variety of anaesthetic drugs have a profound effect on the migration and actions of leucocytes, but the mechanisms are unclear. One proposed mechanism is the inhibition of intracellular transcription factors and second messenger cascades. For example, barbiturates inhibit the activation of nuclear transcription factor κB (a key regulator of immune function) when TNF receptors are stimulated in human T-cells [1], seemingly by binding directly to the calmodulin/calcineurin complex. This further downregulates the transport of nuclear factor of activated T-cells (NFAT) into the nucleus and hence diminishes T-lymphocyte function [2]. These effects are strongly dependent on the structure of the barbiturate used, and could not be replicated with propofol.

An alternative mechanism would be a receptor-mediated effect. There is plenty of evidence that leucocytes express receptors that were once thought to be confined to the central nervous system, and at which many anaesthetic drugs are known to act. T-lymphocytes, for example, express functional GABA_A receptors. GABA inhibits proinflammatory CD4⁺ T-cell responses in vitro in mice, which can be mimicked by GABA_A agonists and blocked by GABA_A antagonists [3]. A GABA implant maintaining a serum concentration of ~300μM also reduces mice’s ability to mount a delayed type hypersensitivity reaction [3] and slows the onset of diabetes in NOD mice [4]. When applied to murine CD8⁺ T-cells, GABA appears to stimulate the immune response [5].

Other neurotransmitters are also implicated in immunomodulation. Mast cells and platelets can sequester 5-HT from the microenvironment and release it in response to injury and inflammation [6, 7]. It is also reported to modulate T-cell activation and differentiation, appearing to be delivered from dendritic cells to T-cells across the immunological synapse and promote T-cell activation [8]. Stimulation of the efferent vagus nerve dampens macrophage activation in rodent models of endotoxaemia and shock: acetylcholine attenuates the production of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6 and IL-18 by macrophages stimulated with endotoxin [9]. Opioid [10] and NMDA receptors [11] can also be identified on leucocytes.

As well as reviewing these data, I will present my data showing that human monocytes express functional GABA_A receptors. Monocytes transcribe mRNA encoding GABA_A subunits and express the protein as a functional chloride channel. Propofol and thiopental inhibit monocyte chemotaxis in vitro at high but clinically feasible concentrations, and migration can be restored by the GABA_A antagonists bicuculline and picrotoxin. These findings may explain some of the anti-inflammatory effects of GABA_A agonists, which might be beneficial under certain circumstances but might also increase patients’ susceptibility to infections.

1. Loop T. Anesthesiology 2002; 96: 1202.

2. Humar M. Mol Pharmacol 2004; 65: 350.

3. Tian J. J Neuroimmunol 1999; 96: 21.

4. Tian J. J Immunol 2004; 173: 5298.

5. Bergeret M. Biomed Pharmacother 1998; 52: 214.

6. Matsuda H, et al. J Immunol 1997; 158: 2891.

7. Gordon J, et al. Trends Immunol 2003; 24: 438.

8. O'Connell PJ, et al. Blood 2006; 107: 1010.

9. Borovikova LV, et al. Nature 2000; 405: 458.

10. Martin-Kleiner I. Neuroimmunomod 2006; 13: 1.

11. Miglio G. Bioch Bio Res Com 2005; 338: 1875.