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Review
. 2019 Apr 16;50(4):796-811.
doi: 10.1016/j.immuni.2019.03.022.

GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation

Michael Dougan  1 , Glenn Dranoff  2 , Stephanie K Dougan  3
Affiliations
Review

GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation

Michael Dougan et al. Immunity. .

Abstract

The β common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the β common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.

Keywords: GM-CSF; IL-3; IL-5; allergic disease; beta common cytokines; eosinophils; hematopoiesis; tumor immunology.

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Conflict of interest statement

M.D. receives research funding from Novartis Pharmaceuticals, and receives consulting fees from Genentech. G.D. is an employee of Novartis Pharmaceuticals. S.K.D receives research funding from Novartis Pharmaceuticals, Bristol-Myers Squibb, and Eli Lilly. The authors are not aware of any other conflicts that might be perceived as affecting the objectivity of this review.

Figures

Figure 1:
Figure 1:
Timeline of the discovery, characterization and therapeutic targeting of the β common cytokine family
Figure 2:
Figure 2:
Diagram of the GM-CSF receptor and downstream signaling. The functional GM-CSF receptor is a hexameric structure comprising two α chains (GMRα), two intercalated β chains (β common chain) and two molecules of GM-CSF. These complexes associated laterally through GMRα to form a 12-protein complex that is responsible for signaling. Signaling downstream of the GM-CSF receptor depends on JAK2 and activation of STAT5A/B. Additionally, mutually exclusive phosphorylation at Y577 and S585 (mediated by PI3K) recruit either 14-3-3 at low concentrations of GM-CSF (S585) or Shc in the setting of high GM-CSF concentrations, mediating a molecular switch between survival (low) and survival and growth (high). The src family kinase lyn acts as a negative regulator of signaling.
Figure 3:
Figure 3:
Physiologic Roles and Therapeutic Targeting of IL-5 and GM-CSF. Physiologic roles are in black. Therapeutic targeting is in orange.
See this image and copyright information in PMC

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