Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis

Jehan Aram,Nanci Frakich,Mohammed Alrouji,Sergio L Colombo,Bruno Gran,Elena Morandi,David Onion,Ian Spendlove,Cris S Constantinescu,Radu Tanasescu,Amal Samaraweera

doi:10.3390/biomedicines8070226

Abstract

Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine produced by immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. We investigated the expression and regulation of GM-CSF in different immune cells in MS. We also investigated the differentiation and frequency of GM-CSF-producing Th cells that do not co-express interferon (IFN)-γ or interleukin-17 (IL-17) (Th-GM cells) in MS. We found a significant increase in the percentage of GM-CSF-expressing Th cells, Th1 cells, Th-GM cells, cytotoxic T (Tc) cells, monocytes, natural killer (NK) cells, and B cells in PBMC from MS patients stimulated with T cell stimuli. Stimulated PBMC culture supernatants from MS patients contained significantly higher levels of IL-2, IL-12, IL-1β, and GM-CSF and significantly lower levels of transforming growth factor (TGF-)β. Blocking IL-2 reduced the frequency of Th-GM cells in PBMC from MS patients. The frequency of Th-GM cells differentiated in vitro from naïve CD4+ T cells was significantly higher in MS patients and was further increased in MS with IL-2 stimulation. These findings suggest that all main immune cell subsets produce more GM-CSF in MS after in vitro stimulation, which is associated with defective TGF-β and increased IL-2 and IL-12 production. Th-GM cells are increased in MS. GM-CSF may be a potential therapeutic target in MS.

Highlights

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS) characterised by inflammation, demyelination, axonal damage, and gliosis [1]
We show that the percentage of Granulocyte macrophage colony stimulating factor (GM-cerebrospinal fluid (CSF))-expressing stimulated peripheral blood mononuclear cells (PBMC) subsets (Th cells, T cells (Tc) cells, monocytes, natural killer (NK) cells, and B cells) is higher in multiple sclerosis (MS) patients when compared to healthy controls (HCs)
Our aim was to determine if T cell-specific stimulation upregulates GM-CSF in T cells and in other immune cell types in the mixed peripheral bloodblood mononuclear cells cells (PBMC); to investigate whether this upregulation is higher in MS; to identify factors that may be involved in this upregulation; and to determine whether immunoregulatory factors like transforming growth factor (TGF-)β are produced in lower amounts in MS under these conditions

Summary

Introduction

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS) characterised by inflammation, demyelination, axonal damage, and gliosis [1]. Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine that acts on mature myeloid cells to activate them [4,5,6]. It is a haematopoietic growth factor that stimulates the formation of granulocytes and macrophages (mature myeloid cells) from precursor cells in the bone marrow [7]. It is expressed by many cell types, including haematopoietic lineage cells. This suggests that GM-CSF is involved in physiological regulation of these cells [8]

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