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Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection.

Xiao BG, Lu CZ, Link H - J. Cell. Mol. Med. (2007 Nov-Dec)

Bottom Line: G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis.Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration.Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. bgxiao@shmu.edu.cn

ABSTRACT
In the light of the enthusiasm to use of recombinant human granulocyte colony-stimulating factor (G-CSF) for immunomodulation and neuroprotection, it should be remembered that the current knowledge is based on a century of laborious research. G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis. Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration. Here, we describe the immunomodulation and the neuroprotection that can be achieved with G-CSF, and summarize possible mechanisms of G-CSF as a potential therapeutic agent in autoimmune diseases and neurological disorders. Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

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Possible mechanisms of immunomodulation of G-CSF in adaptive immunity.G-CSF induces the expression of both GATA-3 and SOCS3, which control T helper cell differentiation, and directs to Th2 response. G-CSF directly induces the generation of tolerogenic DC, or indirectly drives the production of tolerogenic DC through inducing SOCS3 expression.Tolerogenic DC have the capacity to induce a regulatory T cells or/and Th2 immune responses. Despite our limited knowledge about the molecular mechanisms involved, it is clear that G-CSF treatment results in increase in the number of regulatory T cells and the differentiation of Th2 cells. G-CSF-induced SOCS3 in turn limits G-CSF receptor signalling.
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fig01: Possible mechanisms of immunomodulation of G-CSF in adaptive immunity.G-CSF induces the expression of both GATA-3 and SOCS3, which control T helper cell differentiation, and directs to Th2 response. G-CSF directly induces the generation of tolerogenic DC, or indirectly drives the production of tolerogenic DC through inducing SOCS3 expression.Tolerogenic DC have the capacity to induce a regulatory T cells or/and Th2 immune responses. Despite our limited knowledge about the molecular mechanisms involved, it is clear that G-CSF treatment results in increase in the number of regulatory T cells and the differentiation of Th2 cells. G-CSF-induced SOCS3 in turn limits G-CSF receptor signalling.

Mentions: G-CSF, like each of the other CSFs, exerts its biologic activities through binding to G-CSF-specific, high affinity receptor, which subsequently triggers multiple signalling mechanisms (Fig. 1). In fact, G-CSF promotes neutrophil production and enhances neutrophil production and function by binding to its receptor [25]. The molecular mechanism by which GCSF/G-CSF receptor signalling controls Th1 and Th2 differentiation as well as immune regulation is still poorly understood. It was reported that the T cellspecific transcription factor GATA-3 (GATA-3) was selectively expressed in Th2 cells, but not Th1 cells [26]. GATA-3 controls T helper cell differentiation, and directs to Th2 response [26, 27]. However, little is known about the regulation of GATA-3 expression. GCSF treatment in vivo resulted in the upregulation of GATA-3 expression at both mRNA and protein levels accompanied by an increase of spontaneous IL-4 secretion [24]. GATA-3 activation in CD4+ T cells seems to induce chromatin remodelling of the intergenic regulatory region for the IL-4/IL-13/IL-5 gene cluster [27], directly activating the IL-5 promoter [26] and exhibiting enhancer activity for IL-4 gene expression [28]. In addition to activating a Th2 program, GATA-3 directly inhibited the opposing Th1 immune response most likely by interfering with the IL-12 signal transduction pathway [29].


Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection.

Xiao BG, Lu CZ, Link H - J. Cell. Mol. Med. (2007 Nov-Dec)

Possible mechanisms of immunomodulation of G-CSF in adaptive immunity.G-CSF induces the expression of both GATA-3 and SOCS3, which control T helper cell differentiation, and directs to Th2 response. G-CSF directly induces the generation of tolerogenic DC, or indirectly drives the production of tolerogenic DC through inducing SOCS3 expression.Tolerogenic DC have the capacity to induce a regulatory T cells or/and Th2 immune responses. Despite our limited knowledge about the molecular mechanisms involved, it is clear that G-CSF treatment results in increase in the number of regulatory T cells and the differentiation of Th2 cells. G-CSF-induced SOCS3 in turn limits G-CSF receptor signalling.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401293&req=5

fig01: Possible mechanisms of immunomodulation of G-CSF in adaptive immunity.G-CSF induces the expression of both GATA-3 and SOCS3, which control T helper cell differentiation, and directs to Th2 response. G-CSF directly induces the generation of tolerogenic DC, or indirectly drives the production of tolerogenic DC through inducing SOCS3 expression.Tolerogenic DC have the capacity to induce a regulatory T cells or/and Th2 immune responses. Despite our limited knowledge about the molecular mechanisms involved, it is clear that G-CSF treatment results in increase in the number of regulatory T cells and the differentiation of Th2 cells. G-CSF-induced SOCS3 in turn limits G-CSF receptor signalling.
Mentions: G-CSF, like each of the other CSFs, exerts its biologic activities through binding to G-CSF-specific, high affinity receptor, which subsequently triggers multiple signalling mechanisms (Fig. 1). In fact, G-CSF promotes neutrophil production and enhances neutrophil production and function by binding to its receptor [25]. The molecular mechanism by which GCSF/G-CSF receptor signalling controls Th1 and Th2 differentiation as well as immune regulation is still poorly understood. It was reported that the T cellspecific transcription factor GATA-3 (GATA-3) was selectively expressed in Th2 cells, but not Th1 cells [26]. GATA-3 controls T helper cell differentiation, and directs to Th2 response [26, 27]. However, little is known about the regulation of GATA-3 expression. GCSF treatment in vivo resulted in the upregulation of GATA-3 expression at both mRNA and protein levels accompanied by an increase of spontaneous IL-4 secretion [24]. GATA-3 activation in CD4+ T cells seems to induce chromatin remodelling of the intergenic regulatory region for the IL-4/IL-13/IL-5 gene cluster [27], directly activating the IL-5 promoter [26] and exhibiting enhancer activity for IL-4 gene expression [28]. In addition to activating a Th2 program, GATA-3 directly inhibited the opposing Th1 immune response most likely by interfering with the IL-12 signal transduction pathway [29].

Bottom Line: G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis.Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration.Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. bgxiao@shmu.edu.cn

ABSTRACT
In the light of the enthusiasm to use of recombinant human granulocyte colony-stimulating factor (G-CSF) for immunomodulation and neuroprotection, it should be remembered that the current knowledge is based on a century of laborious research. G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis. Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration. Here, we describe the immunomodulation and the neuroprotection that can be achieved with G-CSF, and summarize possible mechanisms of G-CSF as a potential therapeutic agent in autoimmune diseases and neurological disorders. Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

Show MeSH
Related in: MedlinePlus