Sensory Impairments and Delayed Regeneration of Sensory Axons in Interleukin-6-Deficient Mice

Zhong, Jian; Dietzel, Irmgard D.; Wahle, Petra; Köpf, Manfred; Heumann, Rolf

doi:10.1523/jneurosci.19-11-04305.1999

Cited by 180 publications

(131 citation statements)

References 52 publications

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“…From other models it is known that neural activities of IL-6-like cytokines often depend on soluble receptor (März et al, 1999). A potential role for IL-6 in the inflammatory heat hyperalgesia is further supported by a recent report of a reduced heat sensitivity in IL-6 null mutant mice in the hot plate test (Zhong et al, 1999). Apart from its known signaling through the IL-6R/gp130 system, IL-6 has been found to cooperate with high affinity neurotrophin receptor Trk (tyrosine kinase) signaling mechanisms that are known to regulate the heat-responsive nociceptor phenotype (Sterneck et al, 1996;Bergmann et al, 1998;Koltzenburg et al, 1999).…”

Section: Discussionmentioning

confidence: 88%

“…First, some cytokines, e.g., IL-6 or TNF-␣, are produced by malignant tissue (Takeuchi et al, 1996;Antunovic et al, 1998;Matsushima et al, 1999). IL-6 injection produces hyperalgesia, and in IL-6 Ϫ/Ϫ mutants, heat sensitivity of nociceptors has been shown to be reduced (Zhong et al, 1999). Second, some cytokines such as TNF-␣ or IL-1␤ have been used for adjuvant chemotherapy, but approximately one-half of the treated patients developed pain syndromes and complained about local tenderness at the injection site (Kemeny et al, 1990;Del Mastro et al, 1995;Elkordy et al, 1997).…”

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confidence: 99%

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Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

2000

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Proinflammatory cytokines contribute to the development of inflammatory and neuropathic pain and hyperalgesia in many in vivo models. The rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heatevoked release of calcitonin gene-related peptide from nociceptors in vitro. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any calcitonin gene-related peptide (CGRP) release at normal skin temperature of 32°C. However, the cytokines IL-1␤, tumor necrosis factor (TNF)-␣, and IL-6 but not IL-8 induced a pronounced and transient sensitization of the heat-evoked CGRP release from nociceptors in vitro. This heat sensitization was dose dependent, with EC 50 for IL-1␤ of 2.7 ng/ml and for TNF-␣ of 3.1 ng/ml. The maximum IL-1␤ effect reached almost 600% of the heat-evoked release, and the maximum TNF-␣ effect induced a rise in CGRP release of 350%. In contrast to IL-1␤ and TNF-␣, IL-6 did not induce heat sensitization when applied alone but was only effective in the presence of soluble IL-6 receptor. This suggests a constitutive expression of signaling receptors for TNF and IL-1␤ and the signal transduction molecule gp130 but not IL-6 receptor or IL-8 receptor. Furthermore, the acute cytokine signaling observed in the present study was independent of transcriptional pathways because sensitization occurred on short latency in vitro and under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Our results demonstrate that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy.

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

2000

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“…Rising levels of galanin in sensory neurons contribute to the initiation and maintenance of axonal regeneration in the injured neurons, leading to functional recovery and restoration of appropriate nociception. In sup-port of this molecular cascade, IL-6 knockout mice demonstrate striking similarities to the galanin mutants in terms of deficits in peripheral nerve regeneration after a crush of the sciatic nerve and an attenuation of neuropathic pain (37,46). These findings, therefore, have important implications for the understanding, and potential therapeutic treatment, of peripheral nerve regeneration in response to trauma and sensory neuropathies.…”

Section: Discussionmentioning

confidence: 99%

Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity

Holmes

Mahoney²,

King³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

193

171

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The neuropeptide galanin is expressed developmentally in the dorsal root ganglion (DRG) and is rapidly up-regulated 120-fold after peripheral nerve section in the adult. Here we report that adult mice carrying a loss-of-function mutation in the galanin gene have a 13% reduction in the number of cells in the DRG associated with a 24% decrease in the percentage of neurons that express substance P. These deficits are associated with a 2.8-and 2.6-fold increase in the number of apoptotic cells in the DRG at postnatal days 3 and 4, respectively. After crush injury to the sciatic nerve, the rate of peripheral nerve regeneration is reduced by 35% with associated long-term functional deficits. Cultured DRG neurons from adult mutant mice demonstrate similar deficits in neurite number and length. These results identify a critical role for galanin in the development and regeneration of sensory neurons. D amage to a peripheral nerve causes changes within the cell body that promote neuronal survival, axonal regeneration, and functional recovery. Under favorable conditions, for instance after a crush injury, most nerve fibers successfully regenerate. However, in many clinically relevant circumstances, traumatic or disease-induced nerve injury has a poor outcome with only limited return of function and often with considerable delay. The molecular and cellular interactions that control the degree and rate of peripheral nerve regeneration are poorly understood and remain important clinical and scientific issues.In an attempt to define the mechanisms that regulate neuronal survival and regeneration, we and others have used the approach of studying factors whose expression patterns are known to change in response to injury. One of the most potent changes in the dorsal root ganglion (DRG) after peripheral nerve injury is the 120-fold increase in the levels of the 29-aa neuropeptide galanin (1). Studies have demonstrated that galanin is expressed at high levels in most cells of the developing DRG from day 16 of gestation until shortly after birth (2). In the adult, galanin is expressed at low levels in only 2-3% of DRG cells, which are predominantly small fiber neurons (1). After axotomy, mRNA and peptide are abundantly expressed in 40-50% of all DRG neurons (3) and remain elevated while the nerve is regenerating (1). Similarly, axotomy also up-regulates galanin expression in motor (4) and sympathetic (5) neurons. The rise in expression in the dorsal horn after axotomy is modest compared with the marked elevation in the DRG (6), reflecting an increase in anterograde transport of galanin from the cell body to the site of injury (7), analogous to that described in axotomized sympathetic neurons (8). Despite these findings, there is no direct evidence that galanin plays a role in axonal regeneration after injury.We previously have generated mice carrying a loss-of-function mutation in the galanin gene (9) and most recently have demonstrated that the chronic absence of galanin throughout prenatal and postnatal development causes an atte...

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“…Mice were injected with tamoxifen (2 µg/10 g body weight) for a consecutive 5 d, followed by 5 d of rest. Unilateral sciatic nerve crush was then performed as described previously (Zhong et al, 1999). Adult DRGs were collected and cultured as described previously (Zou et al, 2009).…”

Section: Dorsal Root Crushmentioning

confidence: 99%

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

O’Donovan¹,

Ma²,

Guo³

et al. 2014

J Cell Biol

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Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

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Sensory Impairments and Delayed Regeneration of Sensory Axons in Interleukin-6-Deficient Mice

Cited by 180 publications

References 52 publications

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

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