Human cord blood-derived mast cells synthesize and release I-309 in response to IgE

Abstract

Mast cells are the central mediating cells of allergic reactions. Binding of allergen specific IgE to high affinity IgE receptor (FcεRI) and subsequent binding of allergen by the IgE causes receptor cross-linking and activation. In a study examining the differential gene expression in human cord blood-derived mast cells (CBMCs) mediated by activation of FcεRI both with IgE and IgE followed by cross-linking with α-IgE, the chemokine I-309 was found to be upregulated.

I-309 is the ligand for the CCR8 receptor and is responsible for chemoattraction of TH2 type T-cells. Interestingly, I-309 RNA and protein levels were elevated not only in response to IgE/α-IgE activation but also by IgE alone. In addition, the I-309 levels were augmented by growth of the CBMCs in the presence of the proinflammatory cytokine IL-4. GM-CSF and MIP-1α secretion was also induced by IgE. These results suggest that IgE, through the production and release of cytokines such as I-309, GM-CSF and MIP-1α could promote an inflammatory reaction in the absence of antigen stimulation of mast cells.

Introduction

Mast cells are the central mediating cells of allergic reactions. Binding of allergen specific IgE to high affinity IgE receptor (FcεRI) and subsequent binding of allergen by the IgE causes receptor cross-linking and activation (Yong, 1997). This activation leads to the release of preformed mediators stored in secretory granules. Among these mediators are histamine and mast cell proteases such as tryptase and chymase (Yong, 1997). In addition, activation leads to the de-novo synthesis of other mediators such as leukotrienes and prostaglandins and the production and release of various cytokines and chemokines including tumor necrosis factor-α (TNF-α), granulocyte/macrophage colony-stimulating factor (GM-CSF), monocyte chemotractant protein-1 (MCP-1), interleukin-8 (IL-8) and interleukin-10 (IL-10) (Yong, 1997). The profile of mediators released from activated mast cells in vivo influences the responses of local structural cells but also profoundly contributes to the nature of inflammatory cell infiltrates (Yong, 1997).

Allergic diseases are generally characterized by two phases (Umetsu and DeKruyff, 1997). The early phase allergic response, such as the anaphylactic response, is likely directly manifested through release of preformed mediators from mast cells (Bingham and Austen, 2000). The second, or late phase, response is characterized by inflammatory cell infiltrate and the development of hyperreactivity of various tissues. The cellular influx promoted during the late phase includes eosinophils, T and B lymphocytes, mast cells, basophils and monocytes (Umetsu and DeKruyff, 1997). A prominent modulator of this overall inflammatory response is the CD4⁺ T-cell (Umetsu and DeKruyff, 1997). In particular, the T-cell component of allergic diseases, such as asthma and allergic rhinitis, is predominantly T-helper type 2 (TH2) cells Kaplan, 2001, Umetsu and DeKruyff, 1997. These TH2 cells elaborate a spectrum of cytokines and chemokines (namely IL-4, IL-13, IL-5 and eotaxin) that promote the infiltration of other cell types Kaplan, 2001, Umetsu and DeKruyff, 1997.

I-309 is a C-C chemokine that is the ligand for the chemokine receptor CCR8. I-309 is chemotactic for T-cells, particularly TH2 cells through restricted expression of the CCR8 receptor (Kaplan, 2001). It is postulated that I-309 plays a key role in the progression of various diseases such as asthma, which have a TH2 component. Indeed, a subpopulation of the T-cells infiltrating lung mucosa in allergen-challenged asthmatics express CCR8 (Panina-Bordignon et al., 2001).

In this report we describe the observation that human umbilical cord blood-derived mast cells (CBMCs) produce the T-cell chemotactic chemokine I-309 in response to FcεRI cross-linking. In addition we explore the observation that IgE can induce significant production of I-309, and other cytokines, in the absence of mast cell degranulation.