- Open Access
Interleukin-1 beta and neurotrophin-3 synergistically promote neurite growth in vitro
- Francesco Boato†1, 2,
- Daniel Hechler†3,
- Karen Rosenberger3,
- Doreen Lüdecke3,
- Eva M Peters4, 5,
- Robert Nitsch6 and
- Sven Hendrix1Email author
© Boato et al; licensee BioMed Central Ltd. 2011
Received: 28 October 2011
Accepted: 26 December 2011
Published: 26 December 2011
Pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) are considered to exert detrimental effects during brain trauma and in neurodegenerative disorders. Consistently, it has been demonstrated that IL-1β suppresses neurotrophin-mediated neuronal cell survival rendering neurons vulnerable to degeneration. Since neurotrophins are also well known to strongly influence axonal plasticity, we investigated here whether IL-1β has a similar negative impact on neurite growth. We analyzed neurite density and length of organotypic brain and spinal cord slice cultures under the influence of the neurotrophins NGF, BDNF, NT-3 and NT-4. In brain slices, only NT-3 significantly promoted neurite density and length. Surprisingly, a similar increase of neurite growth was induced by IL-1β. Additionally, both factors increased the number of brain slices displaying maximal neurite growth. Furthermore, the co-administration of IL-1β and NT-3 significantly increased the number of brain slices displaying maximal neurite growth compared to single treatments. These data indicate that these two factors synergistically stimulate two distinct aspects of neurite outgrowth, namely neurite density and neurite length from acute organotypic brain slices.
Interleukin-1 beta (IL-1β) is a member of the IL-1 family of cytokines which have potent pro-inflammatory properties. It is produced in the periphery mainly by monocytes and is a strong activator of the host immune response to both injury and infection [1, 2]. In the central nervous system (CNS) IL-1β is primarily produced by microglia and invading monocytes/macrophages, but other types of resident cells of the nervous system, including neurons and astrocytes, are also capable of its production . It is generally believed that inflammatory processes stimulated by pro-inflammatory cytokines and particularly by IL-1β, are rather detrimental and can aggravate the primary damage caused by infection of the CNS. This has been suggested by various in vivo studies, in line with its enhanced expression in the brain after damage or in neurodegenerative diseases, including Alzheimer's disease (AD). Consistently, IL-1 deficient mice display reduced neuronal loss and infarct volumes after ischemic brain damage  and direct application of the recombinant cytokine results in an enhanced infarct volume . In traumatic brain injury, antibodies against IL-1β reduce the loss of hippocampal neurons . Consistently, in a mouse model of AD, an inhibitor of pro-inflammatory cytokine production suppressed neuroinflammation leading to a restoration of hippocampal synaptic dysfunction markers . In AD it has also been demonstrated that members of the IL-1 family are associated with an increased risk of contracting the disease .
The findings in various in vitro models suggest a rather elaborated mechanism. In culture, IL-1β demonstrated neurotoxic effects towards hippocampal neurons exposed to high concentrations (500 ng/ml) combined with long-term exposure (three days). However, no effect was observed in lower concentrations following short-term exposure (one day) . In other in vitro models, IL-1β has even been seen to display beneficial effects towards neuronal survival in the CNS [10, 11]. This has also been observed in axonal growth in the peripheral nervous system both in vivo following sciatic nerve injury [12, 13] and in vitro in adult dorsal root ganglion (DRG) collagen gel explant cultures , but not in dissociated single DRG neuron cultures .
Previously, it has been demonstrated that IL-1β impairs neurotrophin-induced neuronal cell survival [16, 17]. It has long been hypothesized that cytokine effects on neurite growth may be mediated at least in part by modulating neurotrophin signalling accordingly . In addition to their positive effect on cell death, the neurotrophins Nerve Growth Factor (NGF), Brain-derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and NT-4 have also a well documented impact on axon plasticity and regeneration [19, 20]. This is crucial in the context of CNS insult to provide re-innervation and thus consecutive functional recovery. Based on these observations we investigated whether IL-1β is also a modulator of neurotrophin-induced neurite outgrowth in the CNS in vitro, using organotypic brain and spinal cord slice cultures. The present study shows that surprisingly, IL-1β did not abrogate NT-3-induced neurite outgrowth but conversely showed a significant synergistic effect. These data indicate that IL-1β differentially regulates the effect of NT-3 on neuronal survival and neurite extension.
Materials and methods
Animals and factors
C57BL/6 wildtype mice and IL-1β-deficient mice  were housed in a conventional animal facility (Center for Anatomy, Charité-Universitätsmedizin, Berlin, Germany). All experiments were performed in accordance with German guidelines on the use of laboratory animals. Recombinant neurotrophins NGF, BDNF, NT-3 and NT-4 were used in a concentration of 500 ng/mL (all Tebu-Bio, Offenbach, Germany). Recombinant IL-1β (Tebu-Bio, Offenbach, Germany) was used in concentrations of 5, 50 and 500 ng/mL.
Acute organotypic brain slice culture
The entorhinal slice cultures were prepared from mouse brains at postnatal day 2 as previously described [22–25]. In brief, after decapitation, the entorhinal cortex was dissected in ice-cold preparation medium, containing MEM with L-Glutamine (2 mM) and Trisbase (8 mM). Transverse slices 350 μm thick were cut using a tissue chopper (Bachhofer, Reutlingen, Germany). Collagen was prepared as previously described . Each entorhinal slice was embedded in a drop of collagen matrix on glass slides. The recombinant factors (neurotrophins and IL-1β) were mixed into the sterile cultivation medium containing MEM, 25% HBSS, 25% heat-inactivated normal horse serum, 4 mM L-glutamine, 4 μg/ml insulin (all from Gibco, Karlsruhe, Germany), 2.4 mg/ml glucose (Braun, Melsungen, Germany), 0.1 mg/ml streptomycin, 100 U/ml penicillin, and 800 μg/ml vitamin C (all Sigma-Aldrich, Taufkirchen, Germany). The collagen co-cultures were incubated at 37°C in a humidified atmosphere with 5% CO2. After 48 h in vitro, the collagen slices were analyzed microscopically (Olympus IX70, Hamburg, Germany).
Neurotrophin concentrations were chosen after extensive pilot experiments based on studies by the Kapfhammer group on age-dependent regeneration of entorhinal fibers in mouse slice cultures , which showed that substantially higher concentrations are needed for brain slices compared to primary cell cultures.
Measurement of axonal density and length of organotypic brain slice cultures
To evaluate the axon outgrowth from entorhinal cortex explants, we improved a pragmatic, reliable and reproducible method, with which the axonal density and length was evaluated after two days in culture [23, 27]. Two independent blinded investigators evaluated neurite density on a scale from 0 (no axons) to 3 (multiple axons), at a total magnification of 200, using a 20× Olympus LCPLANFL objective (Olympus IX70, Hamburg, Germany). Axonal length was quantified at a total magnification of 100, using a 10× Olympus LCPLANFL objective and a widefield eyepiece with a grid of 100 × 100 μm (Olympus WH 10X2-H, Hamburg, Germany) and by measuring the length of a minimum of 10 axons growing in the same direction and reaching the same length: grade 0 (0 - 200 μm), 1 (200 - 400 μm), 2 (400 - 800 μm) and 3 (> 800 μm). Slices with a score equal 3 in length or density, where considered as having "maximum growth" and were then used for further analysis. For combined "maximum density and length" analysis, only the slices which reached the maximum score in both parameters were selected. All experiments were repeated at least three times.
Acute organotypic transverse spinal cord slice cultures
Transverse spinal cord cultures were prepared from mice at embryonic stage 13 (E13). After preparation out of the amniotic sac, embryos were decapitated and skin and organs were removed to isolate the spinal column, it was immediately transferred into ice cold HBSS medium. After dissection of the spinal cord, the remaining dorsal root ganglia (DRG) were removed and lumbar and cervical spinal sections dismissed. The thoracic segment was cut with a tissue chopper into 350 μm slices. These slices were divided along the sulcus medianus into two halves and each placed into a drop of collagen (as described above) with the cut surface of the sulcus medianus showing upwards. After polymerization of the collagen, 500 μl of medium with or without factors were added to the slices. The transverse spinal cord slices were incubated at 37°C in a humidified atmosphere with 5% CO2. After 48 h in vitro, the collagen slices were analyzed microscopically (Olympus IX70, Hamburg, Germany).
Measurement of axonal outgrowth from transverse spinal cord slices
Axonal outgrowth of the transverse spinal cord slices was evaluated as described previously for organotypic dorsal root ganglia cultures . Slices were photographed in PBS with two fixed exposure times to visualize the neurite area and the slice, respectively. The ratio between these two areas was calculated and matched between slices with or without factor. All experiments were repeated at least three times.
The results are expressed as mean ± SEM. The values from the experimental cultures were compared to control cultures prepared in the same experiment (double treatment with NT-3 and IL-1β were additionally compared to single treatments). Subsequently, the data of each group were pooled for statistical analysis. After confirming that significant differences existed between the various groups by performing a Kruskal-Wallis Test, p-values were determined, using a Mann-Whitney-U test. A Chi2-test was used to test if the frequency of maximal neurite growth was significantly different between the groups.
Such an increase is not seen after administration of the other neurotrophins (Figure 1A).
Similarly, NT-3 also significantly increased the length of the cortical neurites when compared to untreated controls while the other neurotrophins had no effect on neurite length (Figure 1B). Thus, only recombinant NT-3 (but not NGF, BDNF or NT-4) is capable of stimulating neurite outgrowth as well as neurite length from entorhinal cortical neurons (Figure 1E, F). A Chi2 test also revealed a significant increase in the number of slices reaching maximal neurite density and length in the presence of NT-3, compared to untreated controls (Figure 1C, D).
To elucidate whether IL-1β has a suppressive effect not only on neurotrophin-induced neuron survival, but also on neurite growth we co-administrated IL-1β and NT3 to acute brain slices (Figure 4C-E). As shown in Figure 1 and 2, both factors alone stimulated neurite density and extension from organotypic brain slices and the combined administration of IL-1β and NT-3 (both 500 ng/ml) could not further promote the mean neurite density and neurite length (Figure 4C, D). However, the Chi2 test showed that the combination of both factors resulted in a significantly higher number of slices reaching maximal neurite density compared to controls and slices treated only with IL-1β. Additionally, the combination of both factors exerts a similar effect on maximal neurite length when compared to controls and slices treated only with NT-3. Finally, a significantly higher number of slices treated with both factors reached maximal levels of both parameters, i. e. combined maximal density and length, when compared to control and NT-3 treated slices (Figure 4E). Thus, the combined application of NT-3 and IL-1β allowed higher numbers of slices to reach maximum values of density and/or length which was not achieved by the application of the single factors.
In summary, IL-1β promotes increased neurite density and length from organotypic brain slices and does not inhibit NT-3-induced neurite growth, but conversely, it shows a synergistic effect in contrast to its suppressive effect on NT-3-induced neuronal survival [16, 17].
Interleukin-1 beta (IL-1β) is a pluripotent cytokine and a main component of many inflammatory pathways. It is overexpressed after central nervous system (CNS) insult, primarily by microglia and macrophages, as part of the local tissue reaction [3, 29, 30]. Increased levels of the cytokine are documented both in chronic neurodegenerative disease and after acute mechanical injury. To examine its effect on neurodegeneration, studies have focused mainly over the last two decades, on Alzheimer's disease (AD) . Elevated plasma levels of IL-1 had been reported in patients with AD (almost 40-fold higher than in the healthy brain) and there is evidence of a correlation between IL-1β gene polymorphism and the risk of contracting the disease [33, 34]. It is currently under investigation as a marker of ongoing brain neurodegeneration, even though levels are also elevated in the healthy aging brain . In line with the documented negative effect on survival, it has been demonstrated that IL-1β impairs NT-3- and BDNF-mediated trophic support of cortical neurons by interfering with the Akt and MAPK/ERK intracellular pathway [16, 17], therefore abrogating their neuroprotective properties.
However, there is increasing evidence that inflammation-associated cytokines can play a key role in stimulating neurite growth and regeneration [18, 36]. As mentioned before, aside from neurodegenerative diseases, IL-1β levels are elevated after mechanical damage to the CNS. Notoriously after mechanical damage in the CNS, two major events occur that slow down or even inhibit regenerative processes. The first is the secondary damage of primarily unharmed neurons, with the second being the intrinsic inhibition of neurite plasticity and reestablishment of a proper neurite network [37–39]. Pro-inflammatory cytokines produced after mechanical damage to the CNS are considered as being negative for neuronal survival and regeneration . However, the role of IL-1β is still controversial, with conflicting in vivo and in vitro data published in the literature . To our knowledge - there is very little literature about the role of IL-1β in axon regeneration in the CNS. In contrast, there is extensive literature about the implication of the neurotrophins Nerve Growth Factor (NGF), Brain-derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and NT-4, in traumatic CNS lesions. These are well known for their neuroprotective effects as well as their ability to promote neurite growth via independent mechanisms [41–44]. The focus of the present study was then to outline whether IL-1β is also able to abrogate neutrophin-induced effects on CNS plasticity, as shown for neutrophin-dependent trophic support for neuronal cell survival.
We started our study by investigating the effect of neurotrophins in a well established model of outgrowth from organotypic brain slices. Surprisingly, only recombinant NT-3 (but not NGF, BDNF or NT-4) was able to stimulate neurite outgrowth as well as neurite length from organotypic brain slices, also increasing the number of slices displaying maximal outgrowth. This is in contrast to several single cell studies in which neurotrophins are highly efficient in promoting axonal growth [45–47]. However, brain slices should be considered as an organotypic model of brain trauma, and therefore appear to be closer to the in vivo situation than single cell cultures [48–50], since the organotypic environment of neurons is composed of astrocytes, microglia cells and other immune cells [25, 51, 52].
Interestingly, we also showed that administration of IL-1β at varying concentrations to the brain slices lead to a significant increase in density and neurite length, when compared to untreated control slices. Key effects of IL-1β in this context include the induction of IL-6, tumor necrosis factor (TNF)-α and nitric oxide  and increased proliferation of macrophages  and astrocytes [55–57]in vitro and in vivo. Both IL-6 and TNF-α are associated with stimulating properties of neurite growth. It was demonstrated that TNF-α can support glia-dependent neurite growth in organotypic mesencephalic brain slices  and is a key factor in the hypothermia induced neurite outgrowth, also as a recombinant factor . The neuropoietic cytokine IL-6 is known to be a potent stimulating factor of neurite growth and regeneration in organotypic hippocampal slices  as well as in dorsal root ganglion cells . Furthermore, IL-1β is capable of activating the production of growth factors in CNS-derived cells. It induces NGF [60–62], fibroblast growth factor (FGF)-2 and S100B production from astrocytes. FGF-2 can be a trophic factor for motor neurons or basal forebrain neurons [63, 64] and IL-1β-induced S100B overexpression is likely to be responsible for the excessive growth of dystrophic neuritis in AD plaques . It was also demonstrated that IL-1β can promote neurite outgrowth from DRGs and cerebellar granule neurons (CGNs) by deactivating the myelin-associated glycoprotein (MAG) RhoA pathway via p38 MAPK activation [12, 13].
In the spinal cord, IL-1β has been implicated in extensive inflammation and progressive neurodegeneration after ischemic and traumatic injury [66, 67]. That is supported by the finding that administration of an IL-1 receptor antagonist reduced both neuronal necrosis and apoptosis in a model of spinal cord ischemic-reperfusion injury in rabbits . Since IL-1β had the capacity to stimulate neurite growth in brain slices, we tested if the same effect could be achieved in a de novo organotypic spinal cord slice model. Surprisingly neither the single administration of IL-1β or NT-3, nor the combined administration of both factors had an influence on the measured neurite growth from the spinal cord slices. These findings may suggest that potent NT-3 effects on neuronal regeneration in the injured spinal cord [69–71] are not the result of modulating segmental spinal cord neurons but rather direct or indirect effects on axons deriving from the motorcortex.
Another difference from the brain situation is that NGF had a stimulating effect on neurite outgrowth from the spinal cord slices which was not present in the entorhinal cortex. This might be due to the time and location dependent regulation of the Trk receptors, influencing the effectiveness of the neurotrophins [72, 73].
As described above, in 2008 the Cotman group presented two publications demonstrating that IL-1β is a negative regulator of neuronal survival, due to its interference with the trophic signalling of NT-3 and BDNF. Previous work of our group indicated that neuronal survival and neurite growth can be two independent phenomena; e.g. while hypothermia has a negative effect on the neuronal survival , we demonstrated that in the same conditions neurite outgrowth is substantially increased and is dependent on tumor necrosis factor (TNF)-α . To test the effect of IL-1β on NT-3-induced neurite growth, we applied both factors on enthorinal cortex slices. Interestingly, even without evident further stimulation in mean density and length compared to the single administration, a Chi square analysis revealed that the double administration leads to a significantly higher number of slices reaching the maximum level of outgrowth (density or length), when compared to the single treatments.
In conclusion, our results demonstrate that NT-3, but not the other neurotrophins, can stimulate neurite growth in organotypic brain slices. In contrast, neither NT-3 nor IL-1β are capable of enhancing neurite growth from spinal cord slices. Furthermore, we were able to demonstrate that the pro-inflammatory cytokine IL-1β has a positive effect on neurite growth from cortical slices and does not abolish the stimulating effect of NT-3, having instead a synergistic effect. As a result anti-inflammatory treatments for AD or mechanical brain damage may have a positive effect on neuronal cell death, with the risk of limiting neurite regrowth.
The authors are indebted to Julia König for her engaged and skillful technical assistance and Dearbhaile Dooley for editing the manuscript. This study was supported in part by grants from the Investitionsbank Berlin (IBB), the Deutsche Forschungsgemeinschaft (SPP1394) and from the Fonds Wetenschappelijk Onderzoek - Vlaanderen (G.0834.11N) to SH
- Peschke T, Bender A, Nain M, Gemsa D: Role of macrophage cytokines in influenza A virus infections. Immunobiology. 1993, 189 (3-4): 340-355. 10.1016/S0171-2985(11)80365-7.PubMedGoogle Scholar
- Hildebrand F, Pape HC, Krettek C: The importance of cytokines in the posttraumatic inflammatory reaction. Unfallchirurg. 2005, 108 (10): 793-794, 796-803. 10.1007/s00113-005-1005-1.PubMedGoogle Scholar
- Bauer J, Berkenbosch F, Van Dam AM, Dijkstra CD: Demonstration of interleukin-1 beta in Lewis rat brain during experimental allergic encephalomyelitis by immunocytochemistry at the light and ultrastructural level. Journal of neuroimmunology. 1993, 48 (1): 13-21. 10.1016/0165-5728(93)90053-2.PubMedGoogle Scholar
- Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ: Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci. 2001, 21 (15): 5528-5534.PubMedGoogle Scholar
- Loddick SA, Rothwell NJ: Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab. 1996, 16 (5): 932-940.PubMedGoogle Scholar
- Lu KT, Wang YW, Yang JT, Yang YL, Chen HI: Effect of interleukin-1 on traumatic brain injury-induced damage to hippocampal neurons. J Neurotrauma. 2005, 22 (8): 885-895. 10.1089/neu.2005.22.885.PubMedGoogle Scholar
- Ralay Ranaivo H, Craft JM, Hu W, Guo L, Wing LK, Van Eldik LJ, Watterson DM: Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci. 2006, 26 (2): 662-670. 10.1523/JNEUROSCI.4652-05.2006.PubMedGoogle Scholar
- Grimaldi LM, Casadei VM, Ferri C, Veglia F, Licastro F, Annoni G, Biunno I, De Bellis G, Sorbi S, Mariani C, et al: Association of early-onset Alzheimer's disease with an interleukin-1alpha gene polymorphism. Ann Neurol. 2000, 47 (3): 361-365. 10.1002/1531-8249(200003)47:3<361::AID-ANA12>3.0.CO;2-N.PubMedGoogle Scholar
- Araujo DM, Cotman CW: Differential effects of interleukin-1 beta and interleukin-2 on glia and hippocampal neurons in culture. Int J Dev Neurosci. 1995, 13 (3-4): 201-212. 10.1016/0736-5748(94)00072-B.PubMedGoogle Scholar
- Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC: Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol. 1999, 163 (7): 3963-3968.PubMedGoogle Scholar
- Diem R, Hobom M, Grotsch P, Kramer B, Bahr M: Interleukin-1 beta protects neurons via the interleukin-1 (IL-1) receptor-mediated Akt pathway and by IL-1 receptor-independent decrease of transmembrane currents in vivo. Mol Cell Neurosci. 2003, 22 (4): 487-500. 10.1016/S1044-7431(02)00042-8.PubMedGoogle Scholar
- Temporin K, Tanaka H, Kuroda Y, Okada K, Yachi K, Moritomo H, Murase T, Yoshikawa H: Interleukin-1 beta promotes sensory nerve regeneration after sciatic nerve injury. Neuroscience letters. 2008, 440 (2): 130-133. 10.1016/j.neulet.2008.05.081.PubMedGoogle Scholar
- Temporin K, Tanaka H, Kuroda Y, Okada K, Yachi K, Moritomo H, Murase T, Yoshikawa H: IL-1beta promotes neurite outgrowth by deactivating RhoA via p38 MAPK pathway. Biochemical and biophysical research communications. 2008, 365 (2): 375-380. 10.1016/j.bbrc.2007.10.198.PubMedGoogle Scholar
- Edoff K, Jerregard H: Effects of IL-1beta, IL-6 or LIF on rat sensory neurons co-cultured with fibroblast-like cells. Journal of neuroscience research. 2002, 67 (2): 255-263. 10.1002/jnr.10092.PubMedGoogle Scholar
- Horie H, Sakai I, Akahori Y, Kadoya T: IL-1 beta enhances neurite regeneration from transected-nerve terminals of adult rat DRG. Neuroreport. 1997, 8 (8): 1955-1959. 10.1097/00001756-199705260-00032.PubMedGoogle Scholar
- Tong L, Balazs R, Soiampornkul R, Thangnipon W, Cotman CW: Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiology of aging. 2008, 29 (9): 1380-1393. 10.1016/j.neurobiolaging.2007.02.027.PubMed CentralPubMedGoogle Scholar
- Soiampornkul R, Tong L, Thangnipon W, Balazs R, Cotman CW: Interleukin-1beta interferes with signal transduction induced by neurotrophin-3 in cortical neurons. Brain research. 2008, 1188: 189-197.PubMed CentralPubMedGoogle Scholar
- Hendrix S, Peters EM: Neuronal plasticity and neuroregeneration in the skin -- the role of inflammation. Journal of neuroimmunology. 2007, 184 (1-2): 113-126. 10.1016/j.jneuroim.2006.11.020.PubMedGoogle Scholar
- Prang P, Del Turco D, Kapfhammer JP: Regeneration of entorhinal fibers in mouse slice cultures is age dependent and can be stimulated by NT-4, GDNF, and modulators of G-proteins and protein kinase C. Exp Neurol. 2001, 169 (1): 135-147. 10.1006/exnr.2001.7648.PubMedGoogle Scholar
- Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001, 24: 677-736. 10.1146/annurev.neuro.24.1.677.PubMed CentralPubMedGoogle Scholar
- Shornick LP, De Togni P, Mariathasan S, Goellner J, Strauss-Schoenberger J, Karr RW, Ferguson TA, Chaplin DD: Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone. The Journal of experimental medicine. 1996, 183 (4): 1427-1436. 10.1084/jem.183.4.1427.PubMedGoogle Scholar
- Hechler D, Boato F, Nitsch R, Hendrix S: Differential regulation of axon outgrowth and reinnervation by neurotrophin-3 and neurotrophin-4 in the hippocampal formation. Exp Brain Res. 2010, 205 (2): 215-221. 10.1007/s00221-010-2355-7.PubMedGoogle Scholar
- Holtje M, Djalali S, Hofmann F, Munster-Wandowski A, Hendrix S, Boato F, Dreger SC, Grosse G, Henneberger C, Grantyn R, et al: A 29-amino acid fragment of Clostridium botulinum C3 protein enhances neuronal outgrowth, connectivity, and reinnervation. FASEB J. 2009, 23 (4): 1115-1126. 10.1096/fj.08-116855.PubMedGoogle Scholar
- Schmitt KR, Boato F, Diestel A, Hechler D, Kruglov A, Berger F, Hendrix S: Hypothermia-induced neurite outgrowth is mediated by tumor necrosis factor-alpha. Brain Pathol. 2010, 20 (4): 771-779.PubMedGoogle Scholar
- Wolf SA, Fisher J, Bechmann I, Steiner B, Kwidzinski E, Nitsch R: Neuroprotection by T-cells depends on their subtype and activation state. Journal of neuroimmunology. 2002, 133 (1-2): 72-80. 10.1016/S0165-5728(02)00367-3.PubMedGoogle Scholar
- Steup A, Lohrum M, Hamscho N, Savaskan NE, Ninnemann O, Nitsch R, Fujisawa H, Puschel AW, Skutella T: Sema3C and netrin-1 differentially affect axon growth in the hippocampal formation. Molecular and cellular neurosciences. 2000, 15 (2): 141-155. 10.1006/mcne.1999.0818.PubMedGoogle Scholar
- Schmitt KR, Kern C, Lange PE, Berger F, Abdul-Khaliq H, Hendrix S: S100B modulates IL-6 release and cytotoxicity from hypothermic brain cells and inhibits hypothermia-induced axonal outgrowth. Neurosci Res. 2007, 59 (1): 68-73. 10.1016/j.neures.2007.05.011.PubMedGoogle Scholar
- Golz G, Uhlmann L, Ludecke D, Markgraf N, Nitsch R, Hendrix S: The cytokine/neurotrophin axis in peripheral axon outgrowth. Eur J Neurosci. 2006, 24 (10): 2721-2730. 10.1111/j.1460-9568.2006.05155.x.PubMedGoogle Scholar
- Sairanen TR, Lindsberg PJ, Brenner M, Siren AL: Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. J Cereb Blood Flow Metab. 1997, 17 (10): 1107-1120.PubMedGoogle Scholar
- Giulian D, Baker TJ, Shih LC, Lachman LB: Interleukin 1 of the central nervous system is produced by ameboid microglia. J Exp Med. 1986, 164 (2): 594-604. 10.1084/jem.164.2.594.PubMedGoogle Scholar
- Shaftel SS, Griffin WS, O'Banion MK: The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 2008, 5: 7-10.1186/1742-2094-5-7.PubMed CentralPubMedGoogle Scholar
- Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, Casadei V, Grimaldi LM: Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain?. Journal of neuroimmunology. 2000, 103 (1): 97-102. 10.1016/S0165-5728(99)00226-X.PubMedGoogle Scholar
- Di Bona D, Plaia A, Vasto S, Cavallone L, Lescai F, Franceschi C, Licastro F, Colonna-Romano G, Lio D, Candore G, et al: Association between the interleukin-1beta polymorphisms and Alzheimer's disease: a systematic review and meta-analysis. Brain Res Rev. 2008, 59 (1): 155-163. 10.1016/j.brainresrev.2008.07.003.PubMedGoogle Scholar
- Licastro F, Pedrini S, Ferri C, Casadei V, Govoni M, Pession A, Sciacca FL, Veglia F, Annoni G, Bonafe M, et al: Gene polymorphism affecting alpha1-antichymotrypsin and interleukin-1 plasma levels increases Alzheimer's disease risk. Ann Neurol. 2000, 48 (3): 388-391. 10.1002/1531-8249(200009)48:3<388::AID-ANA16>3.0.CO;2-G.PubMedGoogle Scholar
- Forlenza OV, Diniz BS, Talib LL, Mendonca VA, Ojopi EB, Gattaz WF, Teixeira AL: Increased serum IL-1beta level in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2009, 28 (6): 507-512. 10.1159/000255051.PubMedGoogle Scholar
- Smorodchenko A, Wuerfel J, Pohl EE, Vogt J, Tysiak E, Glumm R, Hendrix S, Nitsch R, Zipp F, Infante-Duarte C: CNS-irrelevant T-cells enter the brain, cause blood-brain barrier disruption but no glial pathology. Eur J Neurosci. 2007, 26 (6): 1387-1398. 10.1111/j.1460-9568.2007.05792.x.PubMedGoogle Scholar
- Fawcett J: Molecular control of brain plasticity and repair. Prog Brain Res. 2009, 175: 501-509.PubMedGoogle Scholar
- Fitch MT, Silver J: CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol. 2008, 209 (2): 294-301. 10.1016/j.expneurol.2007.05.014.PubMed CentralPubMedGoogle Scholar
- Schwartz M, Kipnis J: Model of acute injury to study neuroprotection. Methods Mol Biol. 2007, 399: 41-53. 10.1007/978-1-59745-504-6_4.PubMedGoogle Scholar
- Gibson RM, Rothwell NJ, Le Feuvre RA: CNS injury: the role of the cytokine IL-1. Vet J. 2004, 168 (3): 230-237. 10.1016/j.tvjl.2003.10.016.PubMedGoogle Scholar
- Lentz SI, Knudson CM, Korsmeyer SJ, Snider WD: Neurotrophins support the development of diverse sensory axon morphologies. J Neurosci. 1999, 19 (3): 1038-1048.PubMedGoogle Scholar
- Patel TD, Jackman A, Rice FL, Kucera J, Snider WD: Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron. 2000, 25 (2): 345-357. 10.1016/S0896-6273(00)80899-5.PubMedGoogle Scholar
- Patel TD, Kramer I, Kucera J, Niederkofler V, Jessell TM, Arber S, Snider WD: Peripheral NT3 signaling is required for ETS protein expression and central patterning of proprioceptive sensory afferents. Neuron. 2003, 38 (3): 403-416. 10.1016/S0896-6273(03)00261-7.PubMedGoogle Scholar
- Goldberg JL, Espinosa JS, Xu Y, Davidson N, Kovacs GT, Barres BA: Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron. 2002, 33 (5): 689-702. 10.1016/S0896-6273(02)00602-5.PubMedGoogle Scholar
- Fryer RH, Kaplan DR, Kromer LF: Truncated trkB receptors on nonneuronal cells inhibit BDNF-induced neurite outgrowth in vitro. Exp Neurol. 1997, 148 (2): 616-627. 10.1006/exnr.1997.6699.PubMedGoogle Scholar
- Bosco A, Linden R: BDNF and NT-4 differentially modulate neurite outgrowth in developing retinal ganglion cells. J Neurosci Res. 1999, 57 (6): 759-769. 10.1002/(SICI)1097-4547(19990915)57:6<759::AID-JNR1>3.0.CO;2-Y.PubMedGoogle Scholar
- Lykissas MG, Batistatou AK, Charalabopoulos KA, Beris AE: The role of neurotrophins in axonal growth, guidance, and regeneration. Curr Neurovasc Res. 2007, 4 (2): 143-151. 10.2174/156720207780637216.PubMedGoogle Scholar
- Heimrich B, Frotscher M: Slice cultures as a model to study entorhinal-hippocampal interaction. Hippocampus. 1993, 3 Spec No: 11-17.PubMedGoogle Scholar
- Noraberg J, Poulsen FR, Blaabjerg M, Kristensen BW, Bonde C, Montero M, Meyer M, Gramsbergen JB, Zimmer J: Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair. Curr Drug Targets CNS Neurol Disord. 2005, 4 (4): 435-452. 10.2174/1568007054546108.PubMedGoogle Scholar
- Hechler D, Nitsch R, Hendrix S: Green-fluorescent-protein-expressing mice as models for the study of axonal growth and regeneration in vitro. Brain Res Rev. 2006, 52 (1): 160-169. 10.1016/j.brainresrev.2006.01.005.PubMedGoogle Scholar
- Heppner FL, Skutella T, Hailer NP, Haas D, Nitsch R: Activated microglial cells migrate towards sites of excitotoxic neuronal injury inside organotypic hippocampal slice cultures. Eur J Neurosci. 1998, 10 (10): 3284-3290. 10.1046/j.1460-9568.1998.00379.x.PubMedGoogle Scholar
- Eyupoglu IY, Savaskan NE, Brauer AU, Nitsch R, Heimrich B: Identification of neuronal cell death in a model of degeneration in the hippocampus. Brain Res Brain Res Protoc. 2003, 11 (1): 1-8. 10.1016/S1385-299X(02)00186-1.PubMedGoogle Scholar
- Lee SC, Dickson DW, Brosnan CF: Interleukin-1, nitric oxide and reactive astrocytes. Brain Behav Immun. 1995, 9 (4): 345-354. 10.1006/brbi.1995.1032.PubMedGoogle Scholar
- Feder LS, Laskin DL: Regulation of hepatic endothelial cell and macrophage proliferation and nitric oxide production by GM-CSF, M-CSF, and IL-1 beta following acute endotoxemia. J Leukoc Biol. 1994, 55 (4): 507-513.PubMedGoogle Scholar
- Giulian D, Lachman LB: Interleukin-1 stimulation of astroglial proliferation after brain injury. Science. 1985, 228 (4698): 497-499. 10.1126/science.3872478.PubMedGoogle Scholar
- Giulian D, Woodward J, Young DG, Krebs JF, Lachman LB: Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J Neurosci. 1988, 8 (7): 2485-2490.PubMedGoogle Scholar
- Giulian D, Young DG, Woodward J, Brown DC, Lachman LB: Interleukin-1 is an astroglial growth factor in the developing brain. J Neurosci. 1988, 8 (2): 709-714.PubMedGoogle Scholar
- Marschinke F, Stromberg I: Dual effects of TNFalpha on nerve fiber formation from ventral mesencephalic organotypic tissue cultures. Brain Res. 2008, 1215: 30-39.PubMed CentralPubMedGoogle Scholar
- Hakkoum D, Stoppini L, Muller D: Interleukin-6 promotes sprouting and functional recovery in lesioned organotypic hippocampal slice cultures. J Neurochem. 2007, 100 (3): 747-757. 10.1111/j.1471-4159.2006.04257.x.PubMedGoogle Scholar
- Lindholm D, Heumann R, Meyer M, Thoenen H: Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature. 1987, 330 (6149): 658-659. 10.1038/330658a0.PubMedGoogle Scholar
- Friedman WJ, Larkfors L, Ayer-LeLievre C, Ebendal T, Olson L, Persson H: Regulation of beta-nerve growth factor expression by inflammatory mediators in hippocampal cultures. J Neurosci Res. 1990, 27 (3): 374-382. 10.1002/jnr.490270316.PubMedGoogle Scholar
- Gadient RA, Cron KC, Otten U: Interleukin-1 beta and tumor necrosis factor-alpha synergistically stimulate nerve growth factor (NGF) release from cultured rat astrocytes. Neurosci Lett. 1990, 117 (3): 335-340. 10.1016/0304-3940(90)90687-5.PubMedGoogle Scholar
- Ho A, Blum M: Regulation of astroglial-derived dopaminergic neurotrophic factors by interleukin-1 beta in the striatum of young and middle-aged mice. Exp Neurol. 1997, 148 (1): 348-359. 10.1006/exnr.1997.6659.PubMedGoogle Scholar
- Albrecht PJ, Dahl JP, Stoltzfus OK, Levenson R, Levison SW: Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival. Exp Neurol. 2002, 173 (1): 46-62. 10.1006/exnr.2001.7834.PubMedGoogle Scholar
- Mrak RE, Griffin WS: Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiology of aging. 2001, 22 (6): 903-908. 10.1016/S0197-4580(01)00287-1.PubMedGoogle Scholar
- Pineau I, Lacroix S: Proinflammatory cytokine synthesis in the injured mouse spinal cord: multiphasic expression pattern and identification of the cell types involved. J Comp Neurol. 2007, 500 (2): 267-285. 10.1002/cne.21149.PubMedGoogle Scholar
- Lu K, Cho CL, Liang CL, Chen SD, Liliang PC, Wang SY, Chen HJ: Inhibition of the MEK/ERK pathway reduces microglial activation and interleukin-1-beta expression in spinal cord ischemia/reperfusion injury in rats. J Thorac Cardiovasc Surg. 2007, 133 (4): 934-941. 10.1016/j.jtcvs.2006.11.038.PubMedGoogle Scholar
- Akuzawa S, Kazui T, Shi E, Yamashita K, Bashar AH, Terada H: Interleukin-1 receptor antagonist attenuates the severity of spinal cord ischemic injury in rabbits. J Vasc Surg. 2008, 48 (3): 694-700. 10.1016/j.jvs.2008.04.011.PubMedGoogle Scholar
- Guo JS, Zeng YS, Li HB, Huang WL, Liu RY, Li XB, Ding Y, Wu LZ, Cai DZ: Cotransplant of neural stem cells and NT-3 gene modified Schwann cells promote the recovery of transected spinal cord injury. Spinal Cord. 2007, 45 (1): 15-24. 10.1038/sj.sc.3101943.PubMedGoogle Scholar
- Johnson PJ, Parker SR, Sakiyama-Elbert SE: Controlled release of neurotrophin-3 from fibrin-based tissue engineering scaffolds enhances neural fiber sprouting following subacute spinal cord injury. Biotechnol Bioeng. 2009, 104 (6): 1207-1214. 10.1002/bit.22476.PubMed CentralPubMedGoogle Scholar
- Shumsky JS, Tobias CA, Tumolo M, Long WD, Giszter SF, Murray M: Delayed transplantation of fibroblasts genetically modified to secrete BDNF and NT-3 into a spinal cord injury site is associated with limited recovery of function. Exp Neurol. 2003, 184 (1): 114-130. 10.1016/S0014-4886(03)00398-4.PubMedGoogle Scholar
- Funakoshi H, Frisen J, Barbany G, Timmusk T, Zachrisson O, Verge VM, Persson H: Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol. 1993, 123 (2): 455-465. 10.1083/jcb.123.2.455.PubMedGoogle Scholar
- Lei L, Parada LF: Transcriptional regulation of Trk family neurotrophin receptors. Cell Mol Life Sci. 2007, 64 (5): 522-532. 10.1007/s00018-006-6328-8.PubMedGoogle Scholar
- Schmitt KR, Kern C, Berger F, Ullrich O, Hendrix S, Abdul-Khaliq H: Methylprednisolone attenuates hypothermia- and rewarming-induced cytotoxicity and IL-6 release in isolated primary astrocytes, neurons and BV-2 microglia cells. Neurosci Lett. 2006, 404 (3): 309-314. 10.1016/j.neulet.2006.05.064.PubMedGoogle Scholar
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