IL-6- and NGF-Induced Rapid Control of Protein Synthesis and Nociceptive Plasticity via Convergent Signaling to the eIF4F Complex

Melemedjian, Ohannes K.; Asiedu, Marina N.; Tillu, Dipti V.; Peebles, Katherine A.; Yan, Jin; Ertz, N.; Dussor, Gregory; Price, Theodore J.

doi:10.1523/jneurosci.3947-10.2010

Cited by 195 publications

(261 citation statements)

References 59 publications

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“…However, correlations do exist between IL-6 signaling and pain processing, even in the absence of soluble IL-6R. It has been reported that IL-6 and NGF have synergistic effects on nociceptive plasticity (Cafferty et al, 2004;Melemedjian et al, 2010). It is therefore possible that NGF promotes expression of IL-6R in TrkA-expressing neurons, and long-term primary culture could also induce IL-6R expression in nociceptors (von Banchet et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Pieraut¹,

Lucas²,

Sangari³

et al. 2011

J. Neurosci.

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The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6 Ϫ/Ϫ mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6 Ϫ/Ϫ dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.

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Section: Discussionmentioning

confidence: 99%

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Pieraut¹,

Lucas²,

Sangari³

et al. 2011

J. Neurosci.

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“…At the level of signaling pathways in peripheral nociceptors, recent studies have shown that mammalian target of rapamycin-(mTOR-) and ERK-dependent pathways play a critical role in chronic pain (10)(11)(12)(13)(14). Models of hyperalgesic priming have been developed as a tool to study the transition to chronic pain (10,15,16).…”

Section: Introductionmentioning

confidence: 99%

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

Heijnen²,

et al. 2013

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Chronic pain is a major clinical problem, yet the mechanisms underlying the transition from acute to chronic pain remain poorly understood. In mice, reduced expression of GPCR kinase 2 (GRK2) in nociceptors promotes cAMP signaling to the guanine nucleotide exchange factor EPAC1 and prolongs the PGE 2 -induced increase in pain sensitivity (hyperalgesia). Here we hypothesized that reduction of GRK2 or increased EPAC1 in dorsal root ganglion (DRG) neurons would promote the transition to chronic pain. We used 2 mouse models of hyperalgesic priming in which the transition from acute to chronic PGE 2 -induced hyperalgesia occurs. Hyperalgesic priming with carrageenan induced a sustained decrease in nociceptor GRK2, whereas priming with the PKCε agonist ΨεRACK increased DRG EPAC1. When either GRK2 was increased in vivo by viral-based gene transfer or EPAC1 was decreased in vivo, as was the case for mice heterozygous for Epac1 or mice treated with Epac1 antisense oligodeoxynucleotides, chronic PGE 2 -induced hyperalgesia development was prevented in the 2 priming models. Using the CFA model of chronic inflammatory pain, we found that increasing GRK2 or decreasing EPAC1 inhibited chronic hyperalgesia. Our data suggest that therapies targeted at balancing nociceptor GRK2 and EPAC1 levels have promise for the prevention and treatment of chronic pain.

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“…This has been particularly evident in growing axons, both for developing and regenerating axons, but there are several publications supporting the notion that mRNAs and ribosomes are present in mature axons of neurons in the peripheral nervous system (PNS) prior to injury (Ben-Yaakov et al, 2012;Hanz et al, 2003;Koenig et al, 2000;Perlson et al, 2005;Yudin et al, 2008;Zelená, 1970). Studies of cutaneous nerve terminals also suggest that translation of mRNAs can be triggered by pain invoking stimuli (Jimenez-Diaz et al, 2008;Melemedjian et al, 2010). In developing axons, translation of new proteins is needed for response to some guidance cues (Jung et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Axonal transport of neural membrane protein 35 mRNA increases axon growth

Merianda

Vuppalanchi

Yoo

et al. 2013

Journal of Cell Science

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SummaryMany neuronal mRNAs are transported from cell bodies into axons and dendrites. Localized translation of the mRNAs brings autonomy to these processes that can be vast distances from the cell body. For axons, these translational responses have been linked to growth and injury signaling, but there has been little information about local function of individual axonally synthesized proteins. In the present study, we show that axonal injury increases levels of the mRNA encoding neural membrane protein 35 (NMP35) in axons, with a commensurate decrease in the cell body levels of NMP35 mRNA. The 39 untranslated region (39UTR) of NMP35 is responsible for this localization into axons. Previous studies have shown that NMP35 protein supports cell survival by inhibiting Fas-ligand-mediated apoptosis; however, these investigations did not distinguish functions of the locally generated NMP35 protein. Using axonally targeted versus cell-body-restricted NMP35 constructs, we show that NMP35 supports axonal growth, and overexpression of an axonally targeted NMP35 mRNA is sufficient to increase axonal outgrowth.

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IL-6- and NGF-Induced Rapid Control of Protein Synthesis and Nociceptive Plasticity via Convergent Signaling to the eIF4F Complex

Cited by 195 publications

References 59 publications

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

Axonal transport of neural membrane protein 35 mRNA increases axon growth

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