β2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-κB-independent mechanisms

Tan, Kai Soo; Nackley, Andrea G.; Satterfield, Kathryn; Maixner, William; Diatchenko, Luda; Flood, Patrick M.

doi:10.1016/j.cellsig.2006.06.007

Cited by 184 publications

(149 citation statements)

References 62 publications

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“…The contribution of β 2 ARs to enhanced pain sensitivity is in line with results from previous studies demonstrating that epinephrine activates β 2 ARs located on primary afferent nociceptors and produces a hyperalgesic state in rats (Aley et al 2001;Khasar et al 1999a;Khasar et al 1999b;Khasar et al 2003). Additionally, common variants of the human β 2 AR gene, coding for differences in receptor expression and internalization, are associated with the development of TMJD (Diatchenko et al 2006). Furthermore, there is evidence that β 2 ARs play a functional role in the development of opioid-induced hyperalgesia, a syndrome characterized by increased sensitivity to noxious stimuli following acute and chronic opioid administration (Liang et al 2006;Nackley et al 2006).…”

Section: Comt Inhibition Increases Pain Behavior Via β 2 and β 3 Adresupporting

confidence: 72%

“…Importantly there is emerging evidence that stimulation of MAPKs induces the transcription of TNFα, IL-1β, and IL-6 (Chi et al 2004;Koj 1996). Moreover, a recent report demonstrates that β 2 ARs located on macrophages leads to IL-1β and IL-6 production through ERK1/2-and p38-dependent activation of ATF-1 and ATF-2 transcription factors (Tan et al 2006). Thus, β 2/3 AR-mediated increases in protein kinase stimulation and proinflammatory cytokine production are not independent processes.…”

Section: Potential Signaling Mechanisms Whereby β 2/3 Receptors Mediamentioning

confidence: 99%

“…Additionally, common variants of the human β 2 AR gene, coding for differences in receptor expression and internalization, are associated with the development of TMJD (Diatchenko et al 2006). Furthermore, there is evidence that β 2 ARs play a functional role in the development of opioid-induced hyperalgesia, a syndrome characterized by increased sensitivity to noxious stimuli following acute and chronic opioid administration (Liang et al 2006;Nackley et al 2006). Our findings together with this work suggest that the alterations in COMT-dependent pain sensitivity and μ-opioid responses observed by Zubieta and colleagues (2003) may also be influenced by β 2 -adrenergic receptor stimulation.…”

Section: Comt Inhibition Increases Pain Behavior Via β 2 and β 3 Adrementioning

confidence: 99%

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Catechol- O -methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors

Nackley

Tan

Fecho

et al. 2007

Pain

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257

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Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Our group demonstrated that human genetic variants of COMT are predictive for the development of Temporomandibular Joint Disorder (TMJD) and are associated with heightened experimental pain sensitivity (Diatchenko et al. 2005). Variants associated with heightened pain sensitivity produce lower COMT activity. Here we report the mechanisms underlying COMT-dependent pain sensitivity. To characterize the means whereby elevated catecholamine levels, resulting from reduced COMT activity, modulate heightened pain sensitivity, we administered a COMT inhibitor to rats and measured behavioral responsiveness to mechanical and thermal stimuli. We show that depressed COMT activity results in enhanced mechanical and thermal pain sensitivity. This phenomenon is completely blocked by the nonselective β-adrenergic antagonist propranolol or by the combined administration of selective β 2 -and β 3 -adrenergic antagonists, while administration of β 1 -adrenergic, α-adrenergic, or dopaminergic receptor antagonists fail to alter COMT-dependent pain sensitivity. These data provide the first direct evidence that low COMT activity leads to increased pain sensitivity via a β 2/3 -adrenergic mechanism. These findings are of considerable clinical importance, suggesting that pain conditions resulting from low COMT activity and/or elevated catecholamine levels can be treated with pharmacological agents that block both β 2 -and β 3 -adrenergic receptors. Keywords epinephrine; norepinephrine; catecholamines; allodynia; hyperalgesia; carrageenan Catecholamines and enzymatic pathways that regulate the bioavailability of catecholamines influence persistent pain. Adrenergic systems contribute to the pathogenesis of rheumatoid Corresponding Author: Andrea G Neely, Center for Neurosensory Disorders, School of Dentistry, CB 7450, University of North Carolina, Chapel Hill, NC 27599-7450, Phone: (919) 966-2953, Fax: (919) Email: andrea_nackley@dentistry.unc.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPain. Author manuscript; available in PMC 2007 July 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript arthritis in animals, as denervation of sympathetic noradrenergic fibers (Levine et al. 1986a) and depletion of peripheral epinephrine (Coderre et al. 1990) attenuate arthritic responses. Additionally, chronic administration of β-adrenergic receptor (βAR) agonists produces a painful arthritis-like s...

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Section: Comt Inhibition Increases Pain Behavior Via β 2 and β 3 Adresupporting

confidence: 72%

Section: Potential Signaling Mechanisms Whereby β 2/3 Receptors Mediamentioning

confidence: 99%

Section: Comt Inhibition Increases Pain Behavior Via β 2 and β 3 Adrementioning

confidence: 99%

See 1 more Smart Citation

Catechol- O -methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors

Nackley

Tan

Fecho

et al. 2007

Pain

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257

200

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“…Two independent pathways involving either PKA or EPAC, can be activated in cells by cAMP (De Rooij et al, 1998). For example, it has recently been reported that EPAC is involved in IL-6 release in response to activation of the β 2 -adrenergic receptor in the RAW murine macrophage cell line (Tan et al, 2007). In FRTL-5 cells, we demonstrated that EPAC was not implicated in the synergistic effect of cAMP on IL-1 stimulated IL-6 mRNA expression.…”

Section: Discussionmentioning

confidence: 54%

Activation of the cAMP pathway synergistically increases IL-1-induced IL-6 gene expression in FRTL-5 thyroid cells: Involvement of AP-1 transcription factors

Szabo-Fresnais

Blondeau

Pomérance

2008

Molecular and Cellular Endocrinology

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Please cite this article as: Szabo-Fresnais, N., Blondeau, J.-P., Pomérance, M., Activation of the cAMP pathway synergistically increases IL-1-induced IL-6 gene expression in FRTL-5 thyroid cells: Involvement of AP-1 transcription factors, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…In contrast, increased norepinephrine production following stressor exposure induces NFκB activity that activates the immune system and increases cytokine production (Bierhaus et al, 2003). This sympathetic activation of the innate immune system acts via nerve fibers that innervate lymphoid organs that coordinate the innate immune responses to threat via alterations in adrenergic signaling (Nance and Sanders, 2007;Tan et al, 2007). Interestingly, evidence suggests that activation of the parasympathetic nervous system also can modulate the activity of the immune system via alterations in vagal release of acetylcholine from T cells (Tracey, 2009).…”

Section: Mechanisms Of Increased Inflammation In Fearand Anxiety-basementioning

confidence: 99%

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

Michopoulos

Powers

Gillespie

et al. 2016

Neuropsychopharmacol

544

376

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The study of inflammation in fear-and anxiety-based disorders has gained interest as growing literature indicates that proinflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear-and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear-and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.

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β2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-κB-independent mechanisms

Cited by 184 publications

References 62 publications

Catechol- O -methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors

Catechol- O -methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors

Activation of the cAMP pathway synergistically increases IL-1-induced IL-6 gene expression in FRTL-5 thyroid cells: Involvement of AP-1 transcription factors

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

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