Human peripheral blood mononuclear cells express GABAA receptor subunits

Alam, Sabina; Laughton, David L.; Walding, Andrew; Wolstenholme, Adrian J.

doi:10.1016/j.molimm.2005.07.025

Cited by 134 publications

(112 citation statements)

References 24 publications

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“…Through the activation of the GABA receptors, propofol exerts various pharmacological effects, including the inhibition of chemotaxis, phagocytosis, ROS generation, and/or cytokine synthesis in monocytes and macrophages (8,9). Another research has demonstrated that human neutrophils express GABA B , but few GABA A receptors (41). However, the roles of the GABA A and GABA B receptors in the respiratory burst and degranulation of activated human neutrophils are still unknown.…”

Section: Discussionmentioning

confidence: 99%

Propofol Inhibits Superoxide Production, Elastase Release, and Chemotaxis in Formyl Peptide–Activated Human Neutrophils by Blocking Formyl Peptide Receptor 1

Yang

Chung

et al. 2013

The Journal of Immunology

174

200

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Neutrophils play a critical role in acute and chronic inflammatory processes, including myocardial ischemia/reperfusion injury, sepsis, and adult respiratory distress syndrome. Binding of formyl peptide receptor 1 (FPR1) by N-formyl peptides can activate neutrophils and may represent a new therapeutic target in either sterile or septic inflammation. Propofol, a widely used i.v. anesthetic, has been shown to modulate immunoinflammatory responses. However, the mechanism of propofol remains to be established. In this study, we showed that propofol significantly reduced superoxide generation, elastase release, and chemotaxis in human neutrophils activated by fMLF. Propofol did not alter superoxide generation or elastase release in a cell-free system. Neither inhibitors of γ-aminobutyric acid receptors nor an inhibitor of protein kinase A reversed the inhibitory effects of propofol. In addition, propofol showed less inhibitory effects in non-FPR1–induced cell responses. The signaling pathways downstream from FPR1, involving calcium, AKT, and ERK1/2, were also competitively inhibited by propofol. These results show that propofol selectively and competitively inhibits the FPR1-induced human neutrophil activation. Consistent with the hypothesis, propofol inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analog of fMLF, to FPR1 in human neutrophils, differentiated THP-1 cells, and FPR1-transfected human embryonic kidney-293 cells. To our knowledge, our results identify, for the first time, a novel anti-inflammatory mechanism of propofol by competitively blocking FPR1 in human neutrophils. Considering the importance of N-formyl peptides in inflammatory processes, our data indicate that propofol may have therapeutic potential to attenuate neutrophil-mediated inflammatory diseases by blocking FPR1.

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Section: Discussionmentioning

confidence: 99%

Propofol Inhibits Superoxide Production, Elastase Release, and Chemotaxis in Formyl Peptide–Activated Human Neutrophils by Blocking Formyl Peptide Receptor 1

Yang

Chung

et al. 2013

The Journal of Immunology

174

200

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“…Although no direct evidence exists, GABA-A receptors have been evoked to explain part of the anti-inflammatory effect of THP. Proofs of concept are the observations that i) THP per se does not act through the classical intra-nuclear PR but in its action recruits GABA-A receptors (Lambert et al 2003, Belelli & Lambert 2005, ii) this neurotransmitter receptor is also expressed on resident and circulating monocytoid cells of the immune system (Alam et al 2006, Bhat et al 2010 as well as on astrocyte and microglia (Lee et al 2011), and iii) GABA suppresses the reactive response of glia to the inflammatory stimulants LPS and IFN-g by inhibiting induction of inflammatory pathways mediated by NFkB and P38 MAP kinase (Lee et al 2011). Nevertheless, as THP can be reversibly converted to DHP , the recruitment of the classical nuclear PR cannot be radically excluded.…”

Section: Neuroactive Steroids As Neuroinflammatory Modulatorsmentioning

confidence: 99%

Neuroactive steroids, their metabolites, and neuroinflammation

Giatti¹,

Boraso²,

Melcangi³

et al. 2012

Journal of Molecular Endocrinology

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Neuroinflammation represents a common feature of many neurodegenerative diseases implicated both in their onset and progression. Neuroactive steroids act as physiological regulators and protective agents in the nervous system. Therefore, the attention of biomedical research has been recently addressed in evaluating whether neuroactive steroids, such as progestagens, androgens, and estrogens may also affect neuroinflammatory pathways. Observations so far obtained suggest a general anti-inflammatory effect with a beneficial relapse on several neurodegenerative experimental models, thus confirming the potentiality of a neuroprotective strategy based on neuroactive steroids. In this scenario, neuroactive steroid metabolism and the sophisticated machinery involved in their signaling are becoming especially attractive. In particular, because metabolism of neuroactive steroids as well as expression of their receptors is affected during the course of neurodegenerative events, a crucial role of progesterone and testosterone metabolites in modulating neuroinflammation and neurodegeneration may be proposed. In the present review, we will address this issue, providing evidence supporting the hypothesis that the efficacy of neuroactive steroids could be improved through the use of their metabolites.

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“…In recent years reports have emerged indicating that immune cells may express GABA A channels but what physiological role they have is not clear (Alam et al, 2006;Bhat et al, 2010;Bjurstom et al, 2008;ReyesGarcia et al, 2007;Tian et al, 2004). Lenmark and colleagues (Michalkiewicz et al, 2004) have generated congenic Biobreeding (BB) rats that develop spontaneously type 1 diabetes (DR lyp/lyp ) and on the same genetic background BB rats that are diabetes resistant (DR +/+ ).…”

Section: Introductionmentioning

confidence: 99%