Nociceptive Responses in Interleukin-6-Deficient Mice to Peripheral Inflammation and Peripheral Nerve Section

Xu, Xiao‐Jun; Hao, Jing‐Xia; Andell-Jonsson, Siv; Poli, Valeria; Bartfai, Tamás; Wiesenfeld‐Hallin, Zsuzsanna

doi:10.1006/cyto.1997.0243

Cited by 134 publications

(77 citation statements)

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“…Based on the magnitude of changes observed in the above experiments, we propose that IL-6 is one of the most important cytokines in this respect. Consistent with the above, pain sensitivity has been reported to be attenuated in mice lacking IL6 or in wild-type mice after neutralization of endogenous IL-6 (Ferreira et al, 1993;Xu et al, 1997;Murphy et al, 1999). Furthermore, we observed that other cytokine activators of gp130, such as leukemia inhibitory factor (LIF), neither induced heat hypersensitivity in vivo nor sensitized nociceptive neurons in vitro (supplemental Fig.…”

Section: Relevance Of Il-6 For Tumor-associated Pain and Nociceptor Ssupporting

confidence: 87%

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

et al. 2009

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Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC-␦ via Gab1/2/PI 3 K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.

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Section: Relevance Of Il-6 For Tumor-associated Pain and Nociceptor Ssupporting

confidence: 87%

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

et al. 2009

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“…The pronociceptive properties of IL-6 became overt in IL-6 knockout mice. 41 These animals showed reduced thermal and mechanical hyperalgesia after injection of carrageenan into the hindpaws and after nerve lesion as compared with wild-types. Additionally, the blockade of JAK-STAT3 activity by lentiviral-mediated production of the suppressor of cytokine signaling (SOCS) 3 prevented the strong expression of IL-6 and of other factors induced in the spinal cord after nerve lesion in rats and substantially attenuated mechanical allodynia.…”

Section: Pronociceptive Cytokinesmentioning

confidence: 88%

IL-4, JAK-STAT signaling, and pain

Busch-Dienstfertig

González-Rodríguez

2013

JAK-STAT

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“…Apart from controlling immune cell interactions, IL-6 may account for the pain and hypersensitivity associated with inflammation, neuropathy or cancer by directly regulating the gain of pain-sensing neurons. IL-6-/-mice present with reduced thermal hyperalgesia after carrageenan inflammation or nerve constriction [138][139][140]. Antisera neutralizing endogenous IL-6 inhibit inflammatory hyperalgesia [141].…”

Section: Interleukin-6mentioning

confidence: 99%

Nociceptor Sensitization by Proinflammatory Cytokines And Chemokines

Kress¹

2010

TOPAINJ

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Cytokines are small proteins with a molecular mass lower than 30 kDa. They are produced and secreted on demand, have a short life span and only travel over short distances if not released into the blood circulation. In addition to the classical interleukins and the chemotactic chemokines, growth factors like VEGF or FGF and the colony stimulating factors are also considered cytokines since they have pleiotropic actions and regulatory function in the immune system. Despite the redundancy and pleiotropy of the cytokine network, specific actions of individual cytokines and endogenous control mechanisms have been identified. Particular local profiles of the classical proinflammatory cytokines are associated with inflammatory hypersensitivity and suggest an early involvement of TNFα, IL-1ß and IL-6. An increasing number of novel cytokines and the more recently discovered chemokines are being associated with pathological pain states. Besides acting as pro-or anti-inflammatory mediators increasing evidence indicates that cytokines act on nociceptors. Neurons within the nociceptive system express neuronal receptors and specifically bind cytokines or chemokines which regulate neuronal excitability, sensitivity to external stimuli and synaptic plasticity. A first step towards a more mechanistic and individual pain therapeutic strategy could be avoidance of hypersensitive pain processing by either neutralization strategies for the proalgesic cytokines or by shifting the balance in favour of antialgesic members of the cytokine-chemokine network.Keywords: Hypersensitivity, inflammatory pain, unrepathic pain, neuroimmune interaction. HYPERSENSITIVITY AND NOCICEPTOR SENSITI-ZATIONTissue injury and inflammation commonly cause hypersensitivity of the affected body region, so that normally painful stimuli become more painful (hyperalgesia), and those usually associated with nonnoxious sensations evoke pain (allodynia). The neural bases for these sensory phenomena have been explored most extensively using heat injury and experimental arthritis as models. Heat and/or mechanical hypersensitivity is observed after burns, inflammation, nerve lesion and malignant tumour growth. In models of peripheral inflammation hypersensitivity has been attributed to sensitization of myelinated (Adelta) and unmyelinated (C) primary sensory neurons [1] that normally respond to potentially tissue damaging (noxious) stimuli. Since the first report on primary afferent fibres that responded only to damaging stimulation of the skin and therefore were termed nociceptors [2] our knowledge on the function of these fibres and their association with pain has increased substantially. Detailed analyses of nociceptor function have been performed and strict criteria are available for phenotyping distinct classes of nociceptors in mice, rats and men [1,[3][4][5][6]. Nociceptors occupy a prominent functional position in fast information detection, transduction and transmission of potentially noxious stimuli. They can undergo plastic changes and nociceptor ...

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Nociceptive Responses in Interleukin-6-Deficient Mice to Peripheral Inflammation and Peripheral Nerve Section

Cited by 134 publications

References 0 publications

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

IL-4, JAK-STAT signaling, and pain

Nociceptor Sensitization by Proinflammatory Cytokines And Chemokines

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