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      Granulocyte-macrophage colony-stimulating factor negatively regulates early IL-10-mediated responses


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          Treatment of inflammatory disorders relies on the intervention in immune responses thereby restoring homeostasis. IL-10 is a cytokine with therapeutic potential, but until now has not been as successful as previously anticipated. A reason for this may be that IL-10 responsiveness depends on the environment of the inflamed tissue. In this study we investigated whether GM-CSF is able to influence IL-10-mediated responses.


          Dendritic cells and macrophages were differentiated from mouse bone marrow and treated or depleted from GM-CSF prior to analyze their response to IL-10. Activity was assessed by measuring cytokine expression upon lipopolysaccharide stimulation, IL-10-induced signaling and down-stream gene expression.


          This study describes that GM-CSF negatively regulates IL-10-mediated responses.

          Lay abstract

          Over the last couple of decades inflammatory disorders, like autoimmune disease and allergies, are becoming more prevalent in the western world. These inflammatory disorders are characterized by uncontrolled immune responses against harmless antigens or commensal bacteria. Treatment of these diseases relies on the intervention in inflammatory responses and thereby restoring the balance of the immune system. One approach used in the clinic to balance the immune system is by treating patients with molecules used by our own immune system to suppress inflammation, such as IL-10. However, treatment with IL-10 has not been as successful as previously anticipated. In this study we show that a particular signaling molecule of the immune system that contributes to inflammation negatively affects the response of immune cells toward IL-10 and thereby could contribute to the low efficacy of IL-10 treatment.

          Most cited references39

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          Colony-stimulating factors in inflammation and autoimmunity.

          Although they were originally defined as haematopoietic-cell growth factors, colony-stimulating factors (CSFs) have been shown to have additional functions by acting directly on mature myeloid cells. Recent data from animal models indicate that the depletion of CSFs has therapeutic benefit in many inflammatory and/or autoimmune conditions and as a result, early-phase clinical trials targeting granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor have now commenced. The distinct biological features of CSFs offer opportunities for specific targeting, but with some associated risks. Here, I describe these biological features, discuss the probable specific outcomes of targeting CSFs in vivo and highlight outstanding questions that need to be addressed.
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            Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.

            The STAT family of proteins carries out a dual function: signal transduction and activation of transcription. A new family member, Stat3, becomes activated through phosphorylation on tyrosine as a DNA binding protein in response to epidermal growth factor (EGF) and interleukin-6 (IL-6) but not interferon gamma (IFN-gamma). It is likely that this phosphoprotein forms homodimers as well as heterodimers with the first described member of the STAT family, Stat91 (renamed Stat1 alpha), which is activated by the IFNs and EGF. Differential activation of different STAT proteins in response to different ligands should help to explain specificity in nuclear signaling from the cell surface.
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              Stat3 dimerization regulated by reversible acetylation of a single lysine residue.

              Z.-l. Yuan (2005)
              Upon cytokine treatment, members of the signal transducers and activators of transcription (STAT) family of proteins are phosphorylated on tyrosine and serine sites within the carboxyl-terminal region in cells. We show that in response to cytokine treatment, Stat3 is also acetylated on a single lysine residue, Lys685. Histone acetyltransferase p300-mediated Stat3 acetylation on Lys685 was reversible by type I histone deacetylase (HDAC). Use of a prostate cancer cell line (PC3) that lacks Stat3 and PC3 cells expressing wild-type Stat3 or a Stat3 mutant containing a Lys685-to-Arg substitution revealed that Lys685 acetylation was critical for Stat3 to form stable dimers required for cytokine-stimulated DNA binding and transcriptional regulation, to enhance transcription of cell growth-related genes, and to promote cell cycle progression in response to treatment with oncostatin M.

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                April 2018
                14 February 2018
                : 4
                : 4
                : FSO288
                [1 ]Wageningen University & Research, Plant Sciences Department, Laboratory of Nematology, Wageningen, The Netherlands
                Author notes
                *Author for correspondence: Tel.: +31 031 748 5261; Fax: +31 031 748 4254; ruud.wilbers@ 123456wur.nl
                © 2018 Wageningen University & Research

                This work is licensed under a Creative Commons Attribution 4.0 License

                : 26 October 2017
                : 09 January 2018
                : 14 February 2018
                Short Communication

                dendritic cells,granulocyte-macrophage colony-stimulating factor (gm-csf),interleukin-10 (il-10),macrophages,signal transduction


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