Stimulation of β2-adrenergic receptors inhibits calcineurin activity in CD4+ T cells via PKA–AKAP interaction

Riether, Carsten; Kavelaars, Annemieke; Wirth, Timo; Pacheco-López, Gustavo; Doenlen, Raphaël; Willemen, Hanneke L.D.M.; Heijnen, Cobi J.; Schedlowski, Manfred; Engler, Harald

doi:10.1016/j.bbi.2010.07.248

Cited by 57 publications

(44 citation statements)

References 60 publications

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“…S3). This agrees with previous work that β-adrenergic receptors on T cells underlie the mechanism of adrenergic splenic nerve signaling (26–28). …”

supporting

confidence: 93%

“…Together with previous results indicating that splenic nerve endings form synapse-like structures on T lymphocytes (23), the termination of these synaptophysin-positive nerve fibers on ChAT-EGFP + T cells provides an anatomical basis for splenic nerve fibers interacting with acetylcholine-producing T cells. Extensive prior work has established that splenic nerve signals modulate T cell responses by signal transduction through β-adrenergic receptors (26–28). Analysis of mRNA levels of adrenergic receptors β1, β2, and β3 in CD4 + CD44 high CD62L low ChAT-EGFP + spleen cells revealed expression of adrenergic receptors β1 and β2, but not β3 (fig.…”

mentioning

confidence: 99%

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Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit

Rosas-Ballina

Olofsson

Ochani

et al. 2011

Science

1,236

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Neural circuits regulate cytokine production to prevent potentially damaging inflammation. A prototypical vagus nerve circuit, the inflammatory reflex, inhibits tumor necrosis factor–α production in spleen by a mechanism requiring acetylcholine signaling through the α7 nicotinic acetylcholine receptor expressed on cytokine-producing macrophages. Nerve fibers in spleen lack the enzymatic machinery necessary for acetylcholine production; therefore, how does this neural circuit terminate in cholinergic signaling? We identified an acetylcholine-producing, memory phenotype T cell population in mice that is integral to the inflammatory reflex. These acetylcholine-producing T cells are required for inhibition of cytokine production by vagus nerve stimulation. Thus, action potentials originating in the vagus nerve regulate T cells, which in turn produce the neurotransmitter, acetylcholine, required to control innate immune responses.

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“…S3). This agrees with previous work that β-adrenergic receptors on T cells underlie the mechanism of adrenergic splenic nerve signaling (26–28). …”

supporting

confidence: 93%

mentioning

confidence: 99%

Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit

Rosas-Ballina

Olofsson

Ochani

et al. 2011

Science

1,236

1,123

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“…Employing the immunosuppressants cyclophoshamide or cyclosporine A (CsA) as a US demonstrated that the insular cortex and amygdala are central key structures in the behaviorally conditioned suppression of antibody production (Ramirez-Amaya et al, 1996), lymphocyte activity, as well as cytokine production [interleukin (IL)-2, interferon (IFN)-g] and cytokine mRNA expression (Pacheco-Lopez et al, 2005;Schedlowski and Pacheco-Lopez, 2010). Employing the CsA-taste conditioning paradigm, the learned immunosuppressive responses are mediated on the peripheral efferent arm via the splenic nerve via noradrenaline and adrenoceptor-dependent mechanisms (Exton et al, , 1999Pacheco-Lopez et al, 2009;Riether et al, 2011). However, this neuroanatomical pathway with the splenic nerve mediating the learned immunosuppression appears to be just one of many efferent neural routes mobilized during learned immunosuppression, because the learned inhibition of the contact-hypersensitivity reaction (employing the identical CsA-taste paradigm) was independent of sympathetic splenic innervation (Exton et al, 2000).…”

Section: Immunologic Responsesmentioning

confidence: 99%

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

Schedlowski¹,

Enck²,

Rief³

et al. 2015

Pharmacol Rev

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257

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“…One example of this functional connection is behavioral conditioning of immune responses [1][2][3] . Previous studies have reported that behavioral conditioning represents one of the major neurobiological mechanisms underlying placebo effects that potentially influence the course of specific diseases and the response to pharmacological therapy, including immunosuppression [4] .…”

Section: Introductionmentioning

confidence: 99%

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Bauer

Busch²,

Pacheco-López³

et al. 2017

Neuroimmunomodulation

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Objective: We examined the role of behavioral conditioning of immune responses with cyclosporine A (CsA) on the development of Th1/Th17-driven experimental autoimmune uveoretinitis (EAU). Methods: Mice received a 0.2% w/v saccharin solution as conditioned stimulus combined with CsA (20 mg/kg) in 6 association trials at 72-h intervals. For evocation periods, conditioned mice were reexposed to saccharin, whereas the conditioned but not reexposed group received water only. Animals were immunized with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBP_p161-180) peptide in complete Freund adjuvant (CFA) and a concomitant injection of pertussis toxin. Results: In naïve mice subjected to the behavioral conditioning regimen, mitogen-induced interleukin (IL)-2 production was decreased in conditioned mice compared to conditioned but not reexposed animals. Incidence and severity of EAU were not significantly lower in behaviorally conditioned and immunized mice. ELISA analysis of splenocytes revealed a reduced interferon (IFN)-γ/IL-17 ratio in CsA-treated, conditioned but not reexposed, and conditioned animals. The adoptive transfer of antigen-specific splenocytes from animals behaviorally conditioned with CsA to naïve mice decreased the severity of EAU in recipient mice compared to the control group. In vitro activation of splenocytes isolated from immunized mice with agonists targeting TLR2 and NOD2 together with β₂-adrenergic activation (induced by epinephrine, norepinephrine, or salbutamol) resulted in decreased IFN-γ but increased IL-17 immune responses. The β₂-adrenergic antagonist propranolol could restore IFN-γ production, whereas only the norepinephrine-induced increase in IL-17 production was abrogated. Conclusions: We conclude that CsA conditioning in the EAU model mitigates Th1 but enhances Th17 immune responses, and does not ameliorate disease. The results imply that in EAU the mechanism of immune conditioning interacts with CFA components during active immunization, most likely via the TLR2/NOD2 pathway, and induces differentiation of Th17 cells that drive autoimmune diseases.

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Stimulation of β2-adrenergic receptors inhibits calcineurin activity in CD4+ T cells via PKA–AKAP interaction

Cited by 57 publications

References 60 publications

Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit

Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

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