Production of interleukin-3 by murine central nervous system neurons

Konishi, Y.; Kamegai, Masahiro; Takahashi, K.; Kunishita, Tatsuhide; Tabira, Takeshi

doi:10.1016/0304-3940(94)90814-1

Cited by 27 publications

(17 citation statements)

References 14 publications

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“…Mechanistic evaluation was focused on IL-3 because it showed the most robust release with both stimuli. IL-3 is expressed in neuronal populations (Konishi et al, 1994) and its activity is mediated through cell surface receptors composed of a ligand-binding IL-3Rα subunit and transmembrane IL-3Rβ subunit (Appel et al, 1995). IL-3 exhibits predominantly neuroprotective actions; it protects cortical neurons from amyloid peptide-induced death (Zambrano et al, 2007) and protects neuroprogenitor and adult neurons cells (Luo et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Lim

Beckel

et al. 2016

Front. Cell. Neurosci.

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Mechanical strain due to increased pressure or swelling activates inflammatory responses in many neural systems. As cytokines and chemokine messengers lead to both pro-inflammatory and neuroprotective actions, understanding the signaling patterns triggered by mechanical stress may help improve overall outcomes. While cytokine signaling in neural systems is often associated with glial cells like astrocytes and microglia, the contribution of neurons themselves to the cytokine response is underappreciated and has bearing on any balanced response. Mechanical stretch of isolated neurons was previously shown to trigger ATP release through pannexin hemichannels and autostimulation of P2X7 receptors (P2X7Rs) on the neural membrane. Given that P2X7Rs are linked to cytokine activation in other cells, this study investigates the link between neuronal stretch and cytokine release through a P2X7-dependent pathway. Cytokine assays showed application of a 4% strain to isolated rat retinal ganglion cells (RGCs) released multiple cytokines. The P2X7R agonist BzATP also released multiple cytokines; Interleukin 3 (IL-3), TNF-α, CXCL9, VEGF, L-selectin, IL-4, GM-CSF, IL-10, IL-1Rα, MIP and CCL20 were released by both stimuli, with the release of IL-3 greatest with either stimuli. Stretch-dependent IL-3 release was confirmed with ELISA and blocked by P2X7R antagonists A438079 and Brilliant Blue G (BBG), implicating autostimulation of the P2X7R in stretch-dependent IL-3 release. Neuronal IL-3 release triggered by BzATP required extracellular calcium. The IL-3Rα receptor was expressed on RGCs but not astrocytes, and both IL-3Rα and IL-3 itself were predominantly expressed in the retinal ganglion cell layer of adult retinal sections, implying autostimulation of receptors by released IL-3. While the number of surviving ganglion cells decreased with time in culture, the addition of IL-3 protected against this loss of neurons. Expression of mRNA for IL-3 and IL-3Rα increased in rat retinas stretched with moderate intraocular pressure (IOP) elevation; BBG blocked the rise in IL-3, implicating a role for the P2X7R in transcriptional regulation in vivo. In summary, mechanical stretch triggers release of cytokines from neurons that can convey neuroprotection. The enhancement of these signals in vivo implicates P2X7R-mediated IL-3 signaling as an endogenous pathway that could minimize damage following neuronal exposure to chronic mechanical strain.

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Section: Discussionmentioning

confidence: 99%

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Lim

Beckel

et al. 2016

Front. Cell. Neurosci.

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“…In the mouse, therefore, the ␤cR knockout will affect only GM-CSF and IL-5 signaling (26), not IL-3, which has itself been reported to possess tissue-protective properties. Notably, IL-3 and its receptors (both ␣ and ␤) are locally made (27,28) and act in a neurotrophic and neuroprotective manner (29,30), including protection from spinal motor neuron transection (31). To answer this question, additional experiments using genesilencing technology will need to be performed in another species, e.g., in the rat, for which abundant data relevant to tissue protection have been collected.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptor

Brines

Grasso

Fiordaliso

et al. 2004

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

605

546

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The cytokine erythropoietin (Epo) is tissue-protective in preclinical models of ischemic, traumatic, toxic, and inflammatory injuries. We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective. For example, carbamylated Epo (CEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in a wide variety of in vivo and in vitro models. These observations suggest that another receptor is responsible for the tissue-protective actions of Epo. Notably, prior investigation suggests that EpoR physically interacts with the common ␤ receptor (␤cR), the signal-transducing subunit shared by the granulocyte-macrophage colony stimulating factor, and the IL-3 and IL-5 receptors. However, because ␤cR knockout mice exhibit normal erythrocyte maturation, ␤cR is not required for erythropoiesis. We hypothesized that ␤cR in combination with the EpoR expressed by nonhematopoietic cells constitutes a tissueprotective receptor. In support of this hypothesis, membrane proteins prepared from rat brain, heart, liver, or kidney were greatly enriched in EpoR after passage over either Epo or CEpo columns but covalently bound in a complex with ␤cR. Further, antibodies against EpoR coimmunoprecipitated ␤cR from membranes prepared from neuronal-like P-19 cells that respond to Epo-induced tissue protection. Immunocytochemical studies of spinal cord neurons and cardiomyocytes protected by Epo demonstrated cellular colocalization of Epo ␤cR and EpoR. Finally, as predicted by the hypothesis, neither Epo nor CEpo was active in cardiomyocyte or spinal cord injury models performed in the ␤cR knockout mouse. These data support the concept that EpoR and ␤cR comprise a tissue-protective heteroreceptor.

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“…The idea of a functional and structural link between the hematopoietic and nervous systems is further supported by the findings that cytokines and cytokine receptors are expressed in both the developing and mature mammalian central nervous system (CNS) 1 (7)(8)(9)(10). In addition, important biological functions have been uncovered for some of these molecules which appear to be mainly implicated in driving or maintaining differentiated properties in specific subpopulations of postmitotic neurons (12)(13)(14).…”

mentioning

confidence: 99%

Activation of the JAK/STAT Pathway Leads to Proliferation of ST14A Central Nervous System Progenitor Cells

Cattaneo

Fraja

Conti

et al. 1996

Journal of Biological Chemistry

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We were interested in whether central nervous system progenitor cells possess the signal transduction machinery necessary to mediate cytokine functions and whether this machinery can become activated upon stable expression of a particular cytokine receptor. For this purpose we utilized a previously obtained conditionally immortalized striatum-derived nestin-positive cell line (ST14A). We found that ST14A cells express Jak2, but not Jak1 or Tyk2. An identical pattern of expression was found in embryonic striatal tissue. To evaluate the susceptibility of these cytokine specific cytoplasmic transducers to activation, ST14A cells were stably transfected with the ␣ and ␤ (AIC2A) chains of the murine interleukin-3 receptor. Four independent lines expressing both the ␣ and ␤ receptor subunits were obtained. We found that cells from each of these lines were induced to proliferate upon exposure to interleukin-3. Dose response curve, antibody blocking experiments and binding studies revealed that the response was mediated by the reconstituted high affinity interleukin-3 receptor. Immunoprecipitation studies on these cells showed that Jak2 and Stat5 were being phosphorylated after stimulation of the reconstituted receptor. These results indicate that members of the JAK/STAT family of proteins are expressed in central nervous system progenitor cells and are susceptible to activation through stimulation of an exogenously expressed cytokine receptor, ultimately leading to cell proliferation.

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Production of interleukin-3 by murine central nervous system neurons

Cited by 27 publications

References 14 publications

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptor

Activation of the JAK/STAT Pathway Leads to Proliferation of ST14A Central Nervous System Progenitor Cells

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