Benzodiazepine anethesia in humans modulates the interleukin-1β, tumor necrosis factor-α and interleukin-6 responses of blood monocytes

doi:10.1016/0165-5728(91)90157-3

Journal of Neuroimmunology

Volume 35, Issues 1–3, December 1991, Pages 13-19

https://doi.org/10.1016/0165-5728(91)90157-3 Get rights and content

Abstract

The influence of sedative and anxiolytic benzodiazepines on human monocyte function was assessed in 11 patients undergoing anesthesia prior to control endoscopy of the urinary tract. A single i.v. injection of 0.08 mg/kg midazolam induced a marked and delayed inhibition of the lipopolysaccharide-induced production of interleukin-1β, tumor necrosis factor-α and interleukin-6 by monocytes isolated from peripheral blood. Corticosteroids were not responsible for the observed immunosuppression. These studies demonstrate that, when administered in man, benzodiazepines markedly alter the capacity of monocytes to synthetize major mediators of the host inflammatory response.

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Cited by (40)

Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling
2019, International Immunopharmacology
Citation Excerpt :
The production of IL-6 from cells can be regulated at multiple steps, including transcription, stabilization of the transcript, translation, and secretion from cells [32–35]. Benzodiazepines have been reported to affect other functions of cytokine production [36,37]. Consistent with the important physiological role of TSPO in immune regulation, it has been reported that microglial TSPO expression is upregulated in inflammatory central nervous system disorders, such as Alzheimer's disease, Parkinson's disease, and intracerebral hemorrhage [38–40].
Benzodiazepines are widely used for anesthesia and sedation and have immunomodulatory properties that may negatively influence clinical outcomes; however, the cellular targets and intermediary signaling pathways involved are unclear. We examined the immunomodulatory effects of the benzodiazepine midazolam on human macrophages and associated molecular mechanisms.
We analyzed effects of midazolam pretreatment on lipopolysaccharide (LPS)-induced upregulation of the costimulatory molecule CD80 and secretion of the pro-inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α, interleukin-10, and nitric oxide (NO) in the human monocyte–macrophage cell line THP-1 and in peripheral monocyte-derived macrophages (PMDMs). The effects of midazolam on NF-κB, IκBα protein, and mitogen-activated protein kinase (MAPK) activation were analyzed in THP-1 cells. We analyzed the involvement of translocator protein (TSPO) in the immunomodulatory effects of midazolam using TSPO ligands. The role of TSPO was investigated using THP-1 cells overexpressing TSPO and THP-1 cells with TSPO knockdown through transfection with small interfering RNA for TSPO.
Midazolam suppressed LPS-induced upregulation of CD80 and release of IL-6 and NO in THP-1 cells and PMDMs. Additionally, midazolam suppressed the activation of NF-κB/AP-1 and MAPKs in human THP-1 cells. The assessed synthetic TSPO ligands showed the same inhibitory effects on macrophage activation as midazolam. Macrophages overexpressing TSPO exhibited enhanced susceptibility to immunosuppression by midazolam, and macrophages lacking TSPO expression exhibited reduced effects of midazolam.
Midazolam inhibits LPS-stimulated immune responses in human macrophages by activating TSPO signaling. Suppression of macrophage activity may contribute to deleterious side effects of benzodiazepines reported in critically ill patients.
Pharmacology of intravenous anesthetics
2018, Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application
Recent advances in molecular pharmacology and neuroscience have led to a greater understanding of how anesthetic chemicals can alter the function of the nervous system. Anesthesia through intravenous agents is a clinical state in which multiple behavioral endpoints are caused by a structurally diverse group of drugs. Certain membrane proteins possess specific binding sites that interact with injectable drugs currently used for clinical anesthesia. This chapter explores what is known and touches on what is unknown regarding the clinical use and neuropharmacologic mechanism of intravenous anesthetics.
GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations
2016, Brain, Behavior, and Immunity
Citation Excerpt :
Specifically, the TSPO is present in the mitochondria coupled to an anion channel, in platelets, lymphocytes, mononuclear cells, endothelium, vascular smooth muscle, mast cells, and also in microglia and neurons. Several in vitro studies have shown that BDZs that bind to the TSPO can affect cellular and immune functions by suppressing cytokine secretion (Taupin et al., 1991; Kim et al., 2006; Joo et al., 2009; Yousefi et al., 2013), modifying cell proliferation, affecting immune cell migration (Ruff et al., 1985) and cellular phagocytic activity (Jin et al., 2013). Immune cells express GABA receptor transcripts and it has been reported GABA treatment decreases the production of pro-inflammatory cytokines in peripheral macrophages (Bhat et al., 2010).
Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b⁺/Ly6C^hi) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and social avoidance behavior in mice subjected to RSD.
C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10 mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD.
Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b⁺/CD45^high) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD.
These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.
Comparison of the effects of xenon and sevoflurane anaesthesia on leucocyte function in surgical patients: A randomized trial
2014, British Journal of Anaesthesia
Citation Excerpt :
Potential bias resulting from side-effects of non-equally distributed immunosuppressive medication was avoided by excluding subjects with steroid medication from data analysis. The immunomodulatory effect of benzodiazepines is well described.20 21 35 Therefore, benzodiazepine premedication was applied to all subjects at the same dosage.
While most anaesthetics are known to suppress immune reactions, data from experimental studies indicate the enhancement of reactivity to inflammatory stimulators under xenon treatment. We investigated the effect of xenon anaesthesia on leucocyte function in surgical patients.
We performed a subgroup analysis of subjects undergoing xenon or sevoflurane anaesthesia in a randomized clinical trial. After oral premedication with midazolam, two separate blood samples were obtained from subjects undergoing elective abdominal surgery, directly before and 1 h after induction of anaesthesia. General anaesthesia was maintained with either 60% xenon or 2.0% sevoflurane in 30% O₂. Leucocyte count, phagocytotic function, and pro-inflammatory cytokine release after ex vivo lipopolysaccharide (LPS) stimulation were determined.
Except for lymphocyte numbers, leucocyte subpopulations did not differ between the groups. Phagocytosis and oxidative burst of granulocytes were reduced in both groups after 1 h of anaesthesia, whereas monocytes were not affected. Pro-inflammatory cytokine release in response to LPS was not affected.
In vivo, xenon and sevoflurane anaesthesia did not have a pro-inflammatory effect, at least in combination with the types of surgery performed in this study. Notably, the impact of xenon anaesthesia did not differ significantly from sevoflurane anaesthesia with regard to leucocyte function. However, an underestimation of treatment effects due to limited sample sizes cannot be fully excluded.
EudraCT 2008-004132-20.
Intravenous Anesthetics
2013, Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application
Effects of different doses and schedules of diazepam treatment on lymphocyte parameters in rats
2010, International Immunopharmacology
Benzodiazepines (BZD) are widely used for the treatment of anxiety. They enhance GABA-ergic neurotransmission through the binding on specific BDZ recognition sites, within the GABA_A receptor-ion channel complex. However, recent studies showed that BZD also act on peripheral benzodiazepine receptor sites (PBR) or translocator protein 18 kDa (TSPO). Evidence for a direct immunomodulatory action for BZD emerged from studies that demonstrated the presence of TSPO on immune/inflammatory cells. The present study was designed to analyze the effects of diazepam on rat lymphocyte parameters, specifically on phenotype, cell proliferation and cell death. The effects of both acute and long-term (21 days) diazepam (1 and 10 mg/kg/day) administrations were evaluated. Results showed that diazepam (1 mg/kg) treatment did not change the immune parameters analyzed. However, both diazepam (10 mg/kg) acute and long-term treatments decreased the number of apoptotic cells; they also increased the percentage of T cytotoxic cells; decreased the percentage of B cells and increased the corticosterone serum levels. The induction of functional tolerance was suggested for the highest dose of diazepam (10 mg/kg), but not for the smaller dose (1 mg/kg) used, at least for diazepam effects on corticosterone serum levels. Diazepam effects were discussed as being related to the number of TSPO sites present on immune cells and/or to the increased levels of serum corticosterone observed after the treatments used.

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Benzodiazepine anethesia in humans modulates the interleukin-1β, tumor necrosis factor-α and interleukin-6 responses of blood monocytes

Abstract

Clin. Immunol. Immunopathol.

Kidney Int.

Immunol. Today

Immunol. Today

Am. J. Med.

Blood

J. Biol. Chem.

Int. J. Immunopharmacol.

Eur. J. Pharmacol.

Blood

Lancet