Pivotal Roles of GM-CSF in Autoimmunity and Inflammation

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Abstract

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor, which stimulates the proliferation of granulocytes and macrophages from bone marrow precursor cells. In autoimmune and inflammatory diseases, Th17 cells have been considered as strong inducers of tissue inflammation. However, recent evidence indicates that GM-CSF has prominent proinflammatory functions and that this growth factor (not IL-17) is critical for the pathogenicity of CD4 ⁺ T cells. Therefore, the mechanism of GM-CSF-producing CD4 ⁺ T cell differentiation and the role of GM-CSF in the development of autoimmune and inflammatory diseases are gaining increasing attention. This review summarizes the latest knowledge of GM-CSF and its relationship with autoimmune and inflammatory diseases. The potential therapies targeting GM-CSF as well as their possible side effects have also been addressed in this review.

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Most cited references 145

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A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

Heon Park, Zhaoxia Li, Xuexian O. Yang … (2005)

Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.

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Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.

T R Mosmann, H Cherwinski, M Bond … (1986)

A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.

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Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

Kamran Ghoreschi, Arian Laurence, Xiang-Ping Yang … (2010)

CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity 1–4 . Crucial for T helper17 (Th17) cells in vivo 5,6 , IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification 7–10 . Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+ Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data suggest an alternative mode for Th17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore have may have therapeutic implications.

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Author and article information

Journal

Journal ID (nlm-ta): Mediators Inflamm

Journal ID (iso-abbrev): Mediators Inflamm

Journal ID (publisher-id): MI

Title: Mediators of Inflammation

Publisher: Hindawi Publishing Corporation

ISSN (Print): 0962-9351

ISSN (Electronic): 1466-1861

Publication date (Print): 2015

Publication date (Electronic): 8 March 2015

Volume: 2015

Electronic Location Identifier: 568543

Affiliations

Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan

Author notes

*Takashi Usui: takausui@ 123456kuhp.kyoto-u.ac.jp

Academic Editor: Fulvio D'Acquisto

Article

DOI: 10.1155/2015/568543

PMC ID: 4370199

PubMed ID: 25838639

SO-VID: e2ed339f-0ca2-4386-abe5-e69ec3ff4ffa

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 5 January 2015

Date accepted : 23 February 2015

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